Abnormal Result

High TSH, low T4.

Presenting Complaint

Intellectual impairment

History

This 17 year old boy from Zimbabwe arrived in South Africa at +/- 8 years of age – diagnosed with hypothyroidism (thyroid dysgenesis)

The thyroid functions have never been well-controlled.

Examination

The patient had significant intellectual impairment – impairment in communication, mother struggling to take care of him, and severly impaired social skills.

Laboratory Investigations

Useful tests to perform to assess for the source of thyroid hormone dysgenesis include:

Tests to assess pituitary function:

• ACTH (or cortisol)
• TSH (would generally be low in pituitary causes of cretinism)
• LH
• FSH
• Growth hormone
• Prolactin (posterior pituitary)

Other Investigations

Thyroid scans (scintigraphy) is not required for diagnosis, but may provide important information on the position of the thyroid.

Thyroid ultrasound is an alternative to determine location of the thyroid gland in the neck, but may fail to detect some tissues.

A lateral radiograph of the knee may be obtained to look for the distal femoral epiphysis; this ossification center appears at about 36 weeks’ gestation, and its absence in a term or postterm infant indicates prenatal effects of hypothyroidism.

Final Diagnosis

Thyroid dysgenesis

Take Home Message

Thyroid biological functions

• Control of basal metabolic rate
• Enhancement of mitochondrial metabolism
• Neural development and growth
• Sexual maturation
• Adrenergic stimulation
• Protein synthesis and carbohydrate metabolism
• Synthesis and degradation of cholesterol and triglycerides
• Increases calcium and phosphate metabolism

Congenital Hypothyroidism’s incidence appears to be 1:2000 – 1:4000 live births – Likely the most common preventable cause of intellectual disability worldwide.

Types / causes:

• Thyroid dysgenesis
• TSH Resistance
• Disordered thyroid hormone secretion or synthesis
• Defect in thyroid hormone transport
• Defects in thyroid hormone metabolism
• Thyroid hormone resistance
• Central hypothryoidism
• Transient congenital hypothyroidism

Newborn screening pre-requisites:

• Direct benefit to the neonate from early dianosis
• This benefit is reasonable balanced against financial and other costs
• There is a reliable test, suitable for neonatal screening
• There is a satisfactory system in place to handle testing, counselling, treatment and follow-up of positive screens.

Criteria for an effective population-wide screening test (e.g. on all
newborns):

1. Availability of a test that is a) cheap and b) reliable
2. Condition is treatable, has high morbidity, and preferably is reasonably common

Criteria required before performing ante-natal diagnostic tests:

1. A reliable and safe diagnostic test is available
2. There is a significant risk of the foetus having the suspected IMD.
3. Condition is serious enough to warrant offering termination and is not treatable.
4. Parents are willing to consider termination of pregnancy if foetus is shown to be affected.

WHO screening criteria (2008)

• The screening programme should respond to a recognized need.
• The objectives of screening should be defined at the outset.
• There should be a defined target population.
• There should be scientific evidence of screening programme effectiveness.
• The program should integrate education, testing, clinical services and programme management.
• There should be quality assurance, with mechanisms to minimize potential risks of screening.
• The program should ensure informed choice, confidentiality and respect for autonomy.
• The program should promote equity and access to screening for the entire target population.
• Program evaluation should be planned from the outset.
• The overall benefits of screening should outweigh the harm.

Newborn screening strategies:

• Test TSH with a reflex T4 if TSH is high
• T4 with reflex TSH if T4 low
• Heel prick (day 2-5 of life) vs cord blood
• Repeat screen at 2-6 weeks?
• Confirmation tests TSH + T4 or fT4

Problems with congenital hypothyroidism screening in South Africa

• Long recall success and high default rate
• Long delays before review and to starting treatment

Only 34% patients are contactable in SA after testing positive (audit by Dr. Michelle Carrihil). Many patients who were recalled – still defaulted.

Treatment

Levothyroxine is the Rx of choice. The aim is to raise T4 and normalise the serum TSH. If given withing the first 2 weeks of life, it can prevent intellectual impairment in >90% of cases.

Conclusion

• This patients intellectual impairment and the associated social implications of this could have been prevented with an effective screening programme.
• Screening programmes despite being projected to be effective, can have many unforeseen difficulties
• Auditing screening programmes regularly and implementing improvements is a necessary part in ensuring its efficacy

References

1. Carrihill, M. 2008. An audit of the thyroid screening programme in the Peninsula Maternal and Neonatal Services. University of Cape Town.
2. https://www.who.int/bulletin/volumes/86/4/07-050112/en/
3. Uptodate section on congenital hypothyroidism
4. BURTIS, C. A., ASHWOOD, E. R., BORDER, B., & TlETZ, N. W. (2001). Tietz fundamentals of clinical chemistry. Philadelphia, WB. Saunders.
5. Medscape section on congenital hypothyroidism

Abnormal Result

TSH<0.01 IU/L, Free-T4 53.1 pmol/L Free-T3: 13.8 pmol/L

Presenting Complaint

G2 P1 GA 30 wks, presented with a large thyroid gland.

Was admitted with uncontrolled hyperthyroidism and congestive cardiac failure.
ECHO: RHD, severe MR, severe TR, EF = 56%
Foetal U/S: normal singleton pregnancy matching with gestational age & no obvious congenital malformations

History

Patient was diagnosed with hyperthyroidism in 2019
Received interrupted courses of NMZ (20 to 30 mg)
Now she is on regular 30 mg NMZ since April 2020, which increased to 40 mg and then to 60 mg in March 2021

Examination

GCS 15/ 15
BP 126/ 63 Pulse 99
Enlarged thyroid mostly Rt lobe with bruit, no eye signs, no enlarged LNs
Had gallop, pan systolic murmur, basal creps and lower leg edema

Laboratory Investigations

Other Investigations

Chest X-ray and CT-chest revealed –> No PE, tracheal narrowing.

U/S thyroid -> A large isoechoic nodule, occupying the whole RT lobe, TIRAD 3.
FNAB RT nodule -> Consistent with cyst, Bethesda 1.

Final Diagnosis

Resistance to antithyroid drugs

Take Home Message

ATDS Resistance, Pregnancy & Lactation

• Antithyroid drugs (ATDS) have been used in clinical practice for more than half a century
• ATDs side effects occur in 3%—5% of patients, the majority of which are allergic reactions such as skin rash, whereas the severe side effects of agranulocytosis (0.15%) and liver failure (<0.1%) are rare.
• Birth defects occurs in 2%—4% of children who have been exposed to MMI in early pregnancy, especially during gestational weeks 6-10.
• MMI, PTU, & CM, all cross the placenta, and can modulates fetal thyroid function. Importantly, all ATDs tend to be more potent in the fetus than in the mother. Thus, when the mother is made euthyroid, the fetus is often over treated.
• Therefore, the aim of treatment is to use the smallest possible dose to maintain maternal TT4/ FT 4 values at, or just above the pregnancy—specific ULM.

Effects of ATDS on pregnancy:

• Drug or class effect
• Daily or cumulative dose
• Time and duration of exposure
• Maternal thyroid function

Timing and type of treatment

A subset of the observational studies performed included a group of children considered as exposed to both MMI and PTU in earlv pregnancy. Half of the studies reported that such ‘double exposure’ was associated with a higher risk of birth defects as compared to non-exposed.

A more detailed evaluation of double exposed cases has indicated that the duration of MMI exposure in early pregnancy is critical. This finding may favor a shift in therapy prior to pregnancy also given that the critical window of exposure is from pregnancy week 6 to 10.

Maternal Thyroid Function

A small subset of observational studies on the use of ATDs and birth defects
provided data on maternal thyroid function in pregnancy.
– However, in one of the cohorts, maternal overt hyperthyroidism was a risk factor for birth defects in the child (adjusted HR: 1.91).
-In the Japanese study (2012), it was also reported that the frequency of birth defects was higher in hypothyroid women compared to euthyroid women.
-In another report from Japan sowed a rate of fetal malformations of:

• 0% (0 of 126) in treated euthyroid women
• 1.7% (2 of 117) in treated hyperthyroid women
• 6% (3 of 50) in untreated hyperthyroid women

Anti-thyroid Drug Resistance

Sporadic cases of resistant thyrotoxicosis are reported.
Etiologies of resistant thyrotoxicosis in literature include type I amiodarone induced thyrotoxicosis (AIT) and Graves disease.
Refractory cases have mostly shown resistance to high dose thionamides and beta-blockers; rarely resistance to iodine has also been reported.

Possible mechanisms responsible for resistance to ATDs include:

• Noncompliance is the most likely culprit
• Drug malabsorption
• Rapid drug metabolism
• Antidrug antibodies
• Impaired intrathyroidal drug accumulation or action
• Predominant elevation of T3 rather than T4 levels

Workup of Patients with Resistant Thyrotoxicosis.

• Evaluation of patient compliance.
• Urinary iodine excretion to exclude iodine contamination
• hilalabsorption of the drug: careful history taking and physical examination.
• Measurement of drug levels and plotting in a normal concentration-time curve
• Measurement of anti-drug antibodies (Recovery test I incubation with Protein-G)
• Intrathyroidal ATDs concentrations (high pressure liquid Chromatography).
• Resistance to drugs can be tested by performing a perchlorate discharge test
• Thyroid peroxidase activity.

Perchlorate discharge test

Perchlorate inhibits NIS function (sodium iodine symporter) eliminating the iodine gradient which is required for maintaining the iodine in the gland. This will results in a partial discharge of radiolabelled iodide from the thyroid indicating an impaired organification.

• A test dose of radioiodine administered first, and then 2 hrs later Potassium perchlorate or
  thiocyanate is administered.
• Perchlorate or thiocyanate is a competitive inhibitor of iodine transport into thyrocyte.
• In normal individuals in whom the organification and coupling remain intact only <10% of radioiodine is discharged (leaked), when iodine transport is inhibited.
• In individuals with defective organification and coupling, 40-90% of radioiodine is discharged (leaked), when iodine transport is inhibited.

Treatment of resistant thyrotoxicosis

Resistant thyrotoxicosis is managed by definitive treatment options: surgery or radioactive iodine ablation after euthyroidism is achieved by ATDs to minimize perioperative adverse events.

No specific guidelines for euthyroidism restoration before definitive treatment and authors have advocated the use of the following adjunctive therapies:

• Iopanoic acid
• Steroids (1 mg/ kg/ day)
• Potassium iodide solution (50—100 mg/d)
• Cholestyramine (4 g TDS)
• Lithium (400 mg twice daily)
• Steroids + Lithium / Steroids + Iopanoic acid
• Plasmapheresis
• Selenium

Practical points:
A dose of up to 90 mg CBZ was used in non-pregnant in literature (ATA recommendation in pregnancy 10 mg to 40 mg).
A dose of 150 mg MMI was used in literature in non-pregnant (ATA recommendation in pregnancy 5 mg to 30 mg)
A dose of 2000 mg PTU was used in literature in non—pregnant (ATA recommendation in pregnancy 100 mg to 600 mg)
The goal of treatment of hyperthyroidism in pregnancy with thionamides is to maintain free T4 in the upper normal range using the lowest possible dosage.
Combination of MMI + PTU was used in the literature

Beta Blockers use in pregnancy

Beta—adrenergic blocking agents, such as propranolol 10 – 40 mg every 6—8 hours may be used for controlling hypermetabolic symptoms.

The dose should be reduced as clinically indicated. In the vast majority of cases the drug can be discontinued in 2—6 weeks.

Long—term treatment with B-blockers adverse effects in pregnancy:
1. Small for gestational age 2.Foetal bradycardia 3.Neonatal hypoglycemia 4.One study suggested a higher spontaneous pregnancy loss rate when both – MMI & BB were taken together compared to patients receiving only MMI.

Abnormal Result

HbA1c = 6.6%

Presenting Complaint

This patient self-presented to a GP and referred to the Pediatric endocrinologist at Red Cross Children’s hospital.

History

The patient, an orphan, had a family history of type 2 DM. The late mother (due to breast CA) and the uncle was confirmed with Type 2 DM. The patient reported self-monitoring of glucose with a point of care device, reported having a glucose at times of 13-14mM. This was thus suspicious for DM2. He reported being active and “running 5-6km on some weekends”.

The patient did not report polyuria, but there was a history of polydipsia occasionally.

Examination

BP elevated, pulse regular, BMI 28.3
Acanthosis nigricans was noted, as well as an oily skin.

The rest of the examination was essentially normal.

Anthropometry: not short, overweight

Laboratory Investigations

HbA1c = 6.6%

An OGTT was done, but unfortunately the glucose was out of stock so we needed to make another plan, thus 50% Dextrose (150ml) was given as the 75g glucose equivalent.

Baseline 4.9 mM; 2h 7.8mM

Criteria for interpretation of Oral GTT (WHO guidelines 1999/2007):
Impaired Fasting Glycaemia:
Fasting plasma glucose 6.1 – 6.9 mmol/L
2 hour glucose during 75g OGTT < 7.8 mmol/L Impaired Glucose Tolerance: Fasting plasma glucose < 7.0 mmol/L 2 hour glucose during 75g OGTT 7.8 – 11.0 mmol/L

Diabetes Mellitus: Fasting plasma glucose >= 7.0 mmol/L OR
2 hour glucose during 75g OGTT >= 11.1 mmol/L

Other Investigations

• TSH normal
• Free-T4 = 11.2 pM
• ALT = Normal and no signs of fatty liver disease (although an ultrasound was not performed).

Central hypothyroidism was also suspected. A synacthen stimulation test can be performed to assess the function, but the fact that the TSH is normal, fairly confidently excludes this diagnosis.

Urine protein:creatinine ratio = normal
Ultrasound not done yet to determine whether there’s a fatty liver

Final Diagnosis

Diabetes Mellitus type 2 in a child, likely a case of MODY (maturity onset diabetes of the young), although this would likely not present itself in a child with the phenotype of a type 2 diabetic child.

Take Home Message

Diabetes Mellitus type 2 is increasing at an enormous rate, even to the extent that children are starting to become affected.

MODY is caused due to a range of genetic diseases involved in insulin signalling and control. The most wel-known gene is most likely that of glucokinase. However, the most prevalent gene affected in MODY-affected individuals is Hepatocyte Nuclear factor 1 alpha (HNF1A) gene. The optimal treatments differ between the different causal genetic defects.

Abnormal Result

• The patient’s calcium measured 2.91 mmol/L on two occasions, with PTH measuring 40.6 pmol/L
• VitD 13.6 (<50 = deficient)
• TFT’s TSH 0.01 T4 26.7pmol/L

Presenting Complaint

Presented at the GIT clinic in Feb 2020 with persistent vomiting and abdominal cramps, which was ongoing since November 2019.

History

• Patient was diagnosed with hypertension in her early 20’s.
• Initiated on HCTZ – subsequently changed to Atenolol 25mg dly – not overweight at the time
• Gastroscopy was normal
• No psychiatric symptoms reported – mood swings are reported occasionally by the family
• Oligomenorrhoea – started in 2019 – nothing else wrong was noted.
• Normal menarche – normal regular menses until the diagnosis of hypertension was made.
• Amenorrhoeic last 4 years on no medication currently

Examination

• Increased BMI – quite significantly increased
• BP 170/90
• Skin: Significant amount of skin tags, acanthosis nigricans
• No striae or bruising
• No Sx of thyroid disease.
• Physical examination unremarkable.
• Normal pulses
• Essentially a normal examination other than the high BMI

Laboratory Investigations

Repeated bloods (5 days after initial presentation): 

• TSH 3.13 T4 12.5
• PTH 28 pmol/L (1.6 -6.9)
• Ca 2.79
• Inorganic phosphate 0.77 L mmol/L (0.78 – 1.42)
• LFT’s: Normal
• Creat Normal
• U-Ca 5.6 (no creatinine to compare ratio)
• FSH 3.2 IU/L
• LH 2.0 IU/L
• E2 244 pmol/L
• Dehydroepiandrosterone sulphate (DHEAS) 2.4 umol/L (1.7 – 9.2)
• Testosterone 0.5 nmol/L (0.3 – 1.7)
• SHBG 25.9 L nmol/L (32.4 – 128.0)
• Prolactin 11.5
• TSH-Receptor antibodies: Negative

Other Investigations

The patient still had occasional vomiting, abdominal cramps and unexplained muscle pain – other electrolytes apart from calcium, magnesium and phosphate is also advised, as is osmolarity as fluid and electrolyte imbalance may be an effect, rather than a cause of the nausea, vomiting and muscle pain – the sodium and potassium was normal however.

See below, for the hypertension, phaeochromocytoma can be excluded by a 24-hour fractionated urinary metanephrines analysis.

Final Diagnosis

• Primary hyperparathyroidism is on top of the differential diagnosis and is likely the cause of the raised total calcium.
• Another cause of the raised blood pressure could very likely be a phaeochromocytoma.
• It was also advised for replacement of Vitamin D, after a repeat measurement.
• Other features of MEN-1 syndrome needs to be excluded.

Take Home Message

For phaeochromocytoma, 3 separate days’ urine collection is recommended if the suspicion is high, which it isn’t in this case. This increases the sensitivity of the test.

Before testing for MEN-1: one needs to correct Calcium first – since the hypercalcemia could exacerbate gastrin levels.

Increased serum calcium and hypophosphatemia is the net-result of increased PTH. Urinary phosphate will also be high if measured.

Abnormal Result

The TSH stayed elevated on our assay (Roche Cobas 6000) with a high-normal free T4.

Presenting Complaint

The patient was seen at the endocrinology OPD for follow-up of her thyroid function tests and review of medications. No acute complaints were noted, but some interesting thyroid function results became known.

History

Previous multinodular goiter with thyrotoxicosis.  Had a complete thyroidectomy March-May 2020.

History of asthma, exema and “other allergies”. 

Current dose of eltroxin = 1.6 ug/kg ~ 100ug/day PO.  The patient (and doctor) declares good compliance to Rx.

Examination

Patient did not have any signs or symptoms of hypo or hyperthyroidism according to the endocrinologist.

Laboratory Investigations

The TSH seems to have stayed elevated on our assay (Roche Cobas 6000) with a high-normal free T4.  The free T3 is normal (which I advised should be measured to assess conversion between the hormones). I also sent the sample to Green Point Laboratory where a Beckman DXi analyser is used with a different antibody set of reagents and a different reference range.

Other Investigations

Auto-immune markers have been requested, since the patient was having prolonged iron deficiency, becoming anaemic, and the clincian raised a suspician of likely celiac disease.

Final Diagnosis

The diagnosis is still unsure, but the likely differential diagnosis is:

1. Decrease in deiodinase activity due to some reason – there are many causes.
2. Decrease in absorbtion of Levothyroxine

Take Home Message

Interference in thyroid function tests are commonly enquired about, especially by endocrinologists. This represents a big portion of our non-routine work and often quite a portion of time is spent on education of clinicians who do not necessarily have a laboratory background. Often, esoteric tests are requested which may not be warranted by the clinical scenario.

This case demonstrates a query raised by a clinician about possible interference in the TFT’s which is warranted. It is important to rule out as best one can, interference in the laboratory assay.

Various ways of determining whether interference is the culprit are:

• Dilution of the sample (in assays where the sample may be diluted – unsuitable for free-T4 as dilution will affect the “free” portion of hormone)
• Running the test on another methodology
• Running the test on another analyzer of the same methodology, but with slight differences, such as a different manufacturer of detection antibodies (e.g. Roche vs. Abbott vs. Siemens vs. Beckman vs. Ortho)
• Precipitating the antibodies e.g. desalting, or PEG-precipitation.
• Binding the antibodies, e.g. protein G or Protein A
• Using of “blocking tubes” which is a proprietary blood collection tube to bind antibodies

Abnormal Result

Grossly increased Methylmalonic acid on urine organic acid analysis

Presenting Complaint

The baby presented as a 1 day neonate at the pediatric OPD with seizures and admitted to ICU.

History

The baby was discharged being normal after birth via a normal vaginal delivery. 24 hours later was brought to the hospital with seizures

Examination

Upon admission the neonate was encephalopathic with uncontrollable seizures.

Laboratory Investigations

Other Investigations

Ammonia in this child was >600 umol/L according to the clinician.

The child was managed as a possible urea cycle defect:

Glucose infusion, preventing catabolism, infusion of vitamins (co-factors). It is unknown whether specifically Vitamin B12 was given as well. Child likely had persistent lactatemia, also evidenced by the high lactate peak in the urine organic acid profile.

The neonate demised after 4 days in the ICU.

Urine organic acid analysis (unfortunately only analysed 2 weeks after demise) demonstrated increased levels of methylmalonic acid, 3-OH propionate, lactate, methylcitrate and a C5 dicarboxylic acid (likely glutarate).

Final Diagnosis

Methylmalonic aciduria

Take Home Message

There are a range of genetic defects causing an increase in Methylmalonic aciduria, but this case likely is

Patients presenting with ketosis, acidosis, and hyperammonemia may have methylmalonic acidemia or another organic acidemia. Evaluation of plasma acylcarnitines and urine organic acids can help to make the diagnosis. Organic acidemias may have a similar presentation, although patients with propionic acidemia may have more severe hyperammonemia than patients with MMA.

Other inherited metabolic disorders that cause elevated serum methylmalonic acid include combined malonic and methylmalonic aciduria, mitochondrial depletion syndrome due to autosomal-recessive pathogenic variants in SUCLA2 or SUCLG1, and also vitamin B12 deficiency.

Abnormal Result

Presenting Complaint

This was a case discussed in consultation with a private consultant:

The patient was admitted with SARS-CoV-2.

History

The clinician was contacted regarding an extremely low LDL-cholesterol, not comparable with the other measurements.

Medication history was unknown at the time when these results became known and had to be authorized.

Examination

Not applicable and information not available.

Laboratory Investigations

Other Investigations

From the results above it becomes clear that there are some discrepancies in the results. The total cholesterol, as measured on the Abbott Allinity (<0.5 mmol/L) does not compare against the measured LDL-cholesterol (3.0 mmol/L), which should be lower than the total cholesterol.

Other investigations to perform on this sample would perhaps be to run it on a different analyser.

Final Diagnosis

The clinician was phoned and it was found that the patient was on high doses of Vitamin C intravenously.

Take Home Message

When there’s a big discrepancy between LDL (measured – directly with a homogenous assay) and the total cholesterol, the cause should be determined, or at least investigated.

The Total cholesterol, LDL-cholesterol, Triglycerides and HDL-cholesterol all use Trinder reactions.

Vitamin C is a quencher in the reaction (likely due to its high anti-oxidant activity). Since COVID has been around, there are quite a lot of protocols of treatment with Vitamin C IV. It is likely that patients infused with IV N-acetylcysteine, also a potent anti-oxidant, will also cause spuriously low total cholesterol. Or perhaps spuriously low results in any reaction employing the trinder reaction.

It is also clear from this case how important it is to discuss results which do not make sense with clinicians.

Summary of the Trinder reaction

A few decades ago, Emerson presented a new color test reaction (Emerson 1943), which is still in common use for the determination of phenolic compounds (e.g. Ettinger et al. 1951; Fiamegos et al. 2002). Later, Trinder adapted this reaction for the determination of blood glucose using horseradish peroxidase (HRP), coupling the hydrogen peroxide produced from the glucose oxidase reaction, to the Emerson indicator reaction (Trinder 1969; Barham & Trinder 1972). For this reason, this reaction is also known as the Trinder reaction. The so-called Emerson–Trinder reaction, is now routinely used as a spectrophotometric indicator reaction in clinical chemistry, in which a quinoneimine dye product is produced by oxidative condensation of a phenol with 4-aminoantipyrine (4-AAP) (Emerson 1943). This indicator reaction was subsequently used for the spectrophotometric assay of a large number of substrates or enzymes (Burtis & Ashwood 1994) such as uric acid (Kabasakalian et al. 1973), cholesterol (Allain et al. 1974), free hemoglobin (Bauer 1981) or triglycerides (Fossati & Prencipe 1982) and also by using different organic hydrogen-donor compounds such as different substituted (ortho, meta and para) chloro or bromophenols, 4-hydroxybenzene-sulfonic acid (Wang et al. 1992), 2,4-dichlorophenol (Klose et al. 1978), 3,5-dichloro-2-hydroxybenzensulfonic acid (Fossati & Prencipe 1982; Fossati et al. 1980) or different aniline derivatives (Tamaoku et al. 1982).

Farzad Deyhimi, Massoud Arabieh & Lida Parvin (2006) Optimization of the Emerson–Trinder enzymatic reaction by response surface methodology, Biocatalysis and Biotransformation, 24:4, 263-271, DOI: 10.1080/10242420600661943

Abnormal Result

Total calcium of 1.47 mmol/L (2.15 – 2.50)

Presenting Complaint

The patient has been having persistent hypocalcemia despite supplementation with calcium.

History

Examination

Not available.

The typical findings in a patient with true hypocalcemia (low ionised calcium) are

Trouseau’s sign

Chvostek’s sign

Laboratory Investigations

Arguably, the first important consideration in patients with low calcium is the albumin. The patient had a mean albumin of 12 g/L, significantly lower than normal (40-50g/L). Arguably, the calcium can be corrected with the well known Payne’s formula to then be 1.47 + (0.02 x (40-12) = 2.03 mmol/L:

Albumin-adjusted calcium (mmol/L) = total calcium (mmol/L) + 0.02 [40 – albumin (g/L)])

Payne RB, Little AJ, Williams RB, Milner JP. Interpretation of serum calcium in patient with abnormal serum proteins. Br Med J. 1973;4:643-646. DOI: 10.1136/bmj.4.5893.643. (View)

Measurement of serum intact parathyroid hormone (PTH) should be performed in all patients with hypocalcemia; it is the most valuable laboratory test for determining the etiology of hypocalcemia:

Vitamin D

Other Investigations

Anti-Tissue Transglutaminase antibodies: Negative: repeated 3 months apart, with sufficient IgA levels in the serum): 0.9 & 0.8 U/mL (EliA c/o: 6.9)

Anti-Gliadin antibodies: Equivocal: 7.8 & 9.6 U/mL (EliA c/o: 6.9)

Anti-endomysial antibodies: Negative

HLA-DQ2: Positive

HLA-DQ8: Negative

Final Diagnosis

Hypocalcemia likely due to malabsorbtion (telangiectasia stated by the clinicians).

Take Home Message

According to International guidelines the following association is expected for patients with Coeliac Disease:
Positive for HLA-DQ2 (HLA-DQA1*05, DQB1*02)
Positive for HLA-DQ8 (HLA-DQA1*03, DQB1*03:02)

Considering the fact that the albumin was high with an increased PTH, the calcium very likely was physiologically also low (bioactive Ca). The Payne’s formula also failed to correct the calcium to the normal reference range.

Abnormal Result

Urine amino acid screening by GCMS demonstrates massive elevations of cystine at 1842 nmol/mg creat (Ref<125), lysine at 10827 nmol/mg creat (Ref < 630) and ornithine at 2742 nmol/mg creat (Ref <91). Dibasic aminoaciduria at these levels is only seen in cystinuria. Our methodology does not detect arginine but in this scenario it would be similarly elevated.

Presenting Complaint

The patient, a 16 y female presented with signs and symptoms of an upper urinary tract infection.

History

No history of chronic medical illness, no medication. Generally have been well.

The patient did have a cousin, following up at Red Cross Children’s Hospital for congenital cystinuria.

Examination

Renal angle tenderness was noted. There were also symptoms of pain which radiated down to the inguinal area.

Laboratory Investigations

Other Investigations

On roentgenological examination, cystine calculi are radiopaque (although not as much) like calcareous calculi, but are more rounded and homogeneous in appearance. They may attain a staghorn size.

Final Diagnosis

Cystinuria – to be genetically confirmed in a case series

Take Home Message

Cystinuria stones develop in patients with homozygous cystinuria. Homozygous cystinuria is characterized by urinary cystine excretion of more than 250 mg/g creatinine.

Aetiology

Cystine is sparingly soluble in urine and it rarely exceeds 1.7mM/liter. Its solubility is greater at higher pH and is enhanced by electrolytes and macromolecules. however, it rarely exceeds 1.7 mM/liter (400 mg/liter). Cystine stones may form when urinary cystine concentration exceeds the solubility of cystine.

Pathophysiology of Cystinuria

Normally, cystine is filtered and almost completely reabsorbed in the proximal nephron, so that less than 20 mg is excreted in urine each day. In cystinuria, the serum concentration and hence the renal filtered load of cystine are reduced. Exaggerated cystine excretion under this circumstance suggests a disturbance in renal handling of cystine. More than one defect can impair tubular reabsorption and back-diffusion of cystine.

Similar defects in transport of other dibasic amino acids are present. However, exaggerated renal excretion of these amino acids and cystine may not be due to a single transport defect. Increasing the filtered load of one of these amino acids does not necessarily augment the excretion of others.

The intestinal transport of dibasic amino acids may also be defective in cystinuria. The disorder has been classified into three types based on varying intestinal transport disturbances for these amino acids. The intestinal transport has been assessed by the in vitro uptake of radiolabeled amino acid by specimens of jejunal mucosa obtained by peroral biopsy and by studies of plasma cystine levels after oral cystine administration. In type I cystinuria, there is no uptake of cystine, lysine, or arginine by jejunal mucosa, and plasma cystine concentration is not elevated after an oral cystine load. Thus there is defective intestinal transport of all three dibasic amino acids. In types II and III, the intestinal transport of dibasic amino acids is disturbed but less severely than in the type I presentation. In type II, some cystine is taken up by jejunal mucosa but at a reduced rate, and oral cystine loading does not increase the plasma cystine level. In type III cystinuria, the uptake of cystine and lysine by jejunal mucosa is variably reduced and the increment in plasma cystine after oral cystine loading is blunted. In the homozygous state, all three types of cystinuria involve excessive renal excretion of all four dibasic amino acids. In the heterozygous state, type I cystinuria is characterized by normal cystine excretion, whereas types II and III have elevated cystine and lysine excretion (although not quite up to the level encountered in the homozygous state), probably because of a prevailing (although reduced) intestinal uptake of these amino acids. Recently, discrete mutations in the dibasic amino acid transporter gene have been found in certain cystinuric patients.

Diagnostic Criteria

The urinary sediment (preferably in fresh first morning void) should be examined for the presence of typical hexagonal cystine crystals. The urine sample should also be screened for “qualitative” cystine by the cyanidenitroprusside test. A positive reaction suggests that cystine excretion exceeds 75 mg/liter. A false-positive test may be encountered in patients with homocystinuria and acetonuria. On roentgenological examination, cystine calculi are radiopaque (although not as much) like calcareous calculi, but are more rounded and homogeneous in appearance. They may attain a staghorn size.

If these studies are suggestive of the presence of cystinuria, urinary cystine excretion should be quantitated. Urinary cystine exceeding 250 mg/g creatinine is usually diagnostic of homozygous cystinuria. Stones passed or removed should be analyzed. The presence of cystine provides a definitive diagnosis of cystinuria.

Treatment of Cystine Nephrolithiasis

A low-methionine diet has often been recommended for the control of cystine nephrolithiasis because methionine is a precursor of cystine. Although such a dietary maneuver may reduce cystine excretion, rigid methionine restriction is impractical. Dietary sodium restriction may also reduce cystine excretion, but this beneficial effect may be neutralized by reduced solubility of cystine resulting from loss of the “solubilizing” action of sodium.

In patients with cystine calculi and moderate cystinuria [1 to 2 mM/day (250 to 500 mg/day)], conservative measures of high fluid intake and alkali administration should be attempted. The aim of fluid therapy is to increase urine volume sufficiently to reduce the cystine concentration below the solubility limit. At least 3 liters of fluid should be provided, including two 8-oz glassfuls with each meal and at bedtime. Patients should be directed to wake up at night to urinate and drink water. Additional fluids should be consumed when excessive sweating or intestinal fluid loss is present. A minimum urine output of 2 liters/day on a consistent basis is attainable by most patients with proper and persistent instruction.

In theory, alkali therapy would enhance cystine solubility by raising urinary pH. However, substantial increases in cystine solubility do not occur until the urinary pH exceeds 7.5. The provision of alkali, no matter how much, rarely raises urinary pH above 7.5. When urinary pH increases above 7.0 with alkali therapy, calcium phosphate nephrolithiasis may be enhanced because of the enhanced urinary supersaturation of hy- droxyapatite in an alkaline environment. Excessive alkali therapy therefore is not indicated.

Thus a modest amount of alkali is recommended to maintain urinary pH in a high normal range (6.5 to 7.0). Potassium citrate has the advantages over sodium citrate that it does not cause hypercalciuria, is less likely to promote development of calcium stones, and does not induce increased cystine excretion.

The object of treatment with penicillamine or tiopronin (α-mercaptopropionylglycine) is to reduce total cystine excretion by complexing cysteine, the monomeric form of cystine. Penicillamine or tiopronin may be added to the conservative treatment program in patients with moderate cystinuria when the conservative treatment is ineffective in controlling stone formation. In patients with severe cystinuria [> 2 mM/day (> 500 mg/day)], in whom conservative management alone is not likely to be effective, penicillamine or tiopronin therapy (together with conservative measures) may be begun.

Penicillamine and tiopronin share with cysteine a free sulfhydryl group. Thus, they undergo thiol-disulfide exchange with cystine to form penicillamine-cysteine or tiopronicysteine disulfide, which is much more soluble than cystine. After oral administration, a sufficient amount of penicillamine or tiopronin can be excreted in urine to complex cysteine and thereby lower cystine excretion. Unfortunately, penicillamine therapy is associated with frequent and sometimes severe side effects,including nephrotic syndrome, dermatitis, and pancytopenia. Tiopronin has biochemical and clinical actions similar to those of penicillamine. However, it has a lower toxicity profile than penicillamine.

Abnormal Result

Presenting Complaint

3week old female.
Sample from Edendale lab.
No clinical info. No lab form available.

History

None available. Unfortunately this is often the case with specimens sent to the laboratory, even for something as complicated as an organic acid analysis.

Examination

None available.

Symptoms and signs of a serious disorder (SUCLA2) where succinate would be raised are:

• early onset low muscle tone
• severe muscular atrophy
• scoliosis
• movement disorders such as dystonia and hyperkinesia
• epilepsy
• growth retardation

Laboratory Investigations

Other Investigations

None known

Final Diagnosis

Bacterial degradation of urine most likely. Hippurate gets degraded to succinate by bacteria. Since there’s no hippurate present in the urine, this is the most likely explanation for this metabolic picture in the urine.

Take Home Message

Succinate is a metabolite very often seen in urine organic acid analyses.

If one sees very high succinate associated with moderate increase in methylmalonate then SUCLA2 must be excluded – a Leigh-like mitochondrial cytopathy.

Methylmalonate was absent in this child’s urine sample – it also increases in this condition.

Mutations in the SUCLA2 gene leading to SUCLA2 deficiency result in Leigh’s or a Leigh-like syndrome with onset of severe hypotonia, muscular atrophy, sensorineural hearing impairment, and often death in early childhood – hence it’s an important condideration, albeit not the aetiology in this child.

Another important fact about succinate is that fumarate (another Krebs cycle intermediate) is usually lower than succinate. Some authors have described that a reversed succinate:fumarate ratio (i.e. fumarate higher than succinate) indicates likely mitochondrial cytopathy. This should further be evaluated if no overt cause can be found.

Although not strictly a patient case, I will discuss the applicability of 3D printing in the laboratory in two particular problems which presented itself in our laboratory.

Case 1

It so happened that a patient pulled the two electrodes of our iontophoresis machine with a forceful jerk, which caused the thin copper cables inside the insulating holder as shown below (cut open afterwards) to sever. See red and black cables below.

A spare cable was fortunately available from Tygerberg Hospital at the time to continue testing patients.

The damage to this cable made the iontophoresis machine unusable. Upon enquiry from the manufacturer, the cable was replaceable but would cost 320 euro (~ZAR5500) and would take weeks to order from Europe. At this bizarre price I reverted to try fix this cable for our laboratory (at least for a spare one should the new one be damaged in the future).

A multimeter was used to test which wires have been damaged and it turned out that 3 of the 4 connecting wires were broken.

Upon removing the thin insulating layers of the wires, the break in the connections were identified and the cables which I had available (recycled from old non-functioning ear phones) were used to solder in place on the connecting electronic chip board. See picture below.

The connecting electronic chip, shown above still needed proper isolation, and since I do have a 3D printer at home, I fairly quickly designed a small isolating box in which the chip would fit.

This was printed with PLA (polylactic acid – a biodegradeable plastic most often used in 3D printing) and the chip was Isolated and the box sealed with a hot glue gun and a soldering iron.

Case 2

While developing a method for Vitamin A measurement on the HPLC, during sample extraction, a batch of samples need to be dried on the Nitrogen Gas dryer. It so happened that the tubes which we used (high volume tubes) did not fit the current heating blocks used.

Our scientist requested I print a set of tube holder blocks to fit the holder for the nitrogen drying gas.

The holes in the aluminium heating blocks could also be drilled bigger and deeper to fit the tubes but that would make them unusable for another application with smaller tubes.

See below:

Apart from 3D printing a new button for our toasted in the communal kitchen, 3D printing 60-well reaction plates for Tissue Immunology etc, I’m often requested by certain people in the lab to print a certain part which is otherwise unobtainable in a reasonable time / at a reasonable cost.

Abnormal Result

Hypernatremia (sodium = 161 mmol/L)

Persistent Hypokalemia (potassium 1.9 mmol/L)

Presenting Complaint

Acute on chronic gastroenteritis

History

• 35 year old female. Known HIV positive on ARV with weight loss. GIT symptoms. To exclude villous atrophy/parasitic infestation.
• This is an HIV positive patient (CD4: 40 cells/uL; viral load: 54 869 copies/mL (4.74 log copies/ml))
• The patient has had a CD4 < 150 since 2018.
• HIV Viral load has never been suppressed <1000 copies / ml.
• There are concerns of ARV compliance

Examination

Not available

Laboratory Investigations

Two days earlier:

Other Investigations

Histological examination requested after colonoscopy: Mild erythema of caecum. To exclude TB/CMV

Patient has undergone a colonoscopy as well as an enteroscopy and mild erythema of the caecum was seen.

The terminal ileum showed: intestinal metaplasia with preserved villous architecture. There is no evidence of active inflammation, ulceration or increased intraepithelial lymphocytes seen. There is no evidence of ova, viral inclusions, granulomas or parasites, and no evidence of dysplasia or malignancy present, hence no pathologic diagnosis.

The caecum biopsy, which was macroscopically erythematous, showed fragments of colonic mucosa with areas of crypt branching and focal gland associated neutrophils.

Final Diagnosis

Mild chronic active colitis.

Take Home Message

This patient, who has laboratory findings of AIDS, likely has a combination of aetiologies accounting for the deranged electrolytes. The acquired immune deficiency likely is complicated by repeated infections with accompanying inflammation of the colonic mucosa – this seems to have been ongoing for months already.

This may well likely have been causing dehydration which recently have caused acute kidney injury, with creatinine rising from a baseline of 86, three weeks prior, to ~250 umol/L.

Some simple bedside laboratory tests may be helpful in aetiological evaluation. In cases where diarrhea has persisted for more than two weeks, testing the stool for glucose and pH can be helpful in identifying those patients with severe villous atrophy. This can be done easily at the bedside with a urine dipstick if available. Glucose test tape, nitrazine paper, and Clinitest tablets also have been used. A stool glucose of greater than 2+ or a pH of less than 5.0 suggests substantial villous atrophy.

Abnormal Result

Fecal osmolar gap 152 mmol/L (<100 mmol/L)

Presenting Complaint

The patient presented with chronic diarrhoea upon which fecal chemistry was requested.

History

The full history is not known.

He presented with an increased anion gap metabolic acidosis a week prior to the stool investigations being requested.

The most common explanation thereof is likely two-fold in the acute setting when the child presented:

• A fasting response with lipolysis and generation of ketone bodies leading to the acidosis
• Dehydration leading to hypoperfusion of tissues with a lactic acidemia
  • Uremia and the increased creatinine in the child was indicative thereof

Examination

Not available

Laboratory Investigations

Stool chemistry:
Faecal sodium 22 mmol/L
Faecal potassium 39.4 mmol/L
Faecal osmolality 275 mOsm/kg
Faecal osmolarity (calculated) 123 mmol/L
Faecal osmolar gap 152 mmol/L
A faecal osmolar gap (the difference between measured and calculated osmolarity) of > 100 mmol/L suggests the presence of poorly absorbed solutes.

Other Investigations

Stool reducing substances: 1+

If a positive stool reducing substances is found, characterization of the reducing substance follows. In our laboratory, this is done by thin layer chromatography.

Final Diagnosis

Chronic (or persistent) diarrhoea: In this case the stool microscopy also showed species of Cryptosporidium, likely the cause of the prolonged diarrhoea. Also the relative lactase deficiency after episodes of enteritis is common due to the lactase enzyme being primarily located at the apical surface of the microvili of the enterocytes, also the common site of infection of various infective organisms, such as cryptosporidium.

Take Home Message

A faecal osmolar gap (the difference between measured and calculated osmolarity) of >100 mmol/L suggests the presence of poorly absorbed solutes. A “quick and dirty” way of excluding this is by doing a dipstick of fecal fluid. In cases where diarrhea has persisted for more than two weeks, testing the stool for glucose and pH can be helpful in identifying those children with severe villous atrophy. This can be done easily at the bedside with a urine dipstick if available. Glucose test tape, nitrazine paper, and Clinitest tablets also have been used. A stool glucose of greater than 2+ or a pH of less than 5.0 suggests substantial villous atrophy.

A low stool osmotic gap suggests secretory diarrhea, wherein the digestive tract is hyperpermeable and losing electrolytes, while a high gap suggests osmotic diarrhea, wherein the digestive tract is unable to absorb solutes from the chyme, either because the digestive tract is hypopermeable (e.g. inflammation), or non-absorbable compounds (e.g. Epsom Salts, Lactose) are present. The reason for this is that secreted sodium and potassium ions make up a greater percentage of the stool osmolality in secretory diarrhea, whereas in osmotic diarrhea, other molecules such as unabsorbed carbohydrates are more significant contributors to stool osmolality.

Abnormal Result

Faecal calprotectin >6000 ug/g stool

Presenting Complaint

59 y male, presenting with diarrhoea and bloody mucus per rectum

History

This is a 59 year old male known with ulcerative colitis proctitis who now has a suspected flare.

Ulcerative colitis (pancolitis) diagnosed 2009.

Histological history

2017: Mild focal active colitis noted on Histology

2019: Sections of rectal mucosa showed features of active chronic proctitis. The crypts showed distortion with focal areas of crypt abscesses noted. The lamina propria was expanded by reactive polymorphous mature lymphocytes with conspicuous eosinophils.

Examination

Unknown

One would look for especially extra-intestinal manifestations of Ulcerative Colitis

Laboratory Investigations

Histology: Sections of colon demonstrate a severe acute colitis with cryptitis , crypt abscess and numerous neutrophils in the lamina propria on a background of chronic changes illustrated by architectural disarray and glandular atrophy. 

Other Investigations

Apart from the colonoscopy and histology, one needs to evaluate for other autoimmune disorders in the gastro-intestinal tract, especially complications of primary sclerosing cholangitis. No biochemical signs thereof was present.

Final Diagnosis

Inflammatory Bowel Disease (Ulcerative colitis)

Take Home Message

We have in recent years started to offer this test. One of our recently qualified pathologists, Dr. Justine Cole, was responsible for the method validation of this assay at our laboratory. There were quite a few difficulties with the validation, mainly due to stool being a difficult to work with matrix and sample stability when transported.

In summary:

Faecal calprotectin is excreted in excess into the intestinal lumen during the inflammatory process and so can act as a marker for inflammatory diseases of the lower gastrointestinal tract. Faecal calprotectin testing is recommended in patients with recent onset lower gastrointestinal symptoms, if cancer is NOT suspected, for the
differential diagnosis of inflammatory bowel disease (IBD e.g., Chrohn’s disease, ulcerative colitis) or irritable bowel syndrome (IBS).

Faecal calprotectin <=50 ug/g stool is negative, i.e., supports IBS.

Faecal calprotectin >50 ug/g stool is positive, i.e., supports IBD.

Abnormal Result

This patient was discussed at a combined Endocrinology / Chemical Pathology meeting.

Total bilirubin: 281 umol/L

Presenting Complaint

The patient was a candidate for a liver transplant, but was referred to the endocrinology department for the short stature and primary amenorrhoea prior to surgery.

History

She was diagnosed with ulcerative colitis in 2016 (@ 12y age) and primary sclerosing cholangitis. Breast development started in 2018 (@14 years), but no menstrual cycles started ever since.

She has one younger sister which is well currently at 4 y age.

Birth weight was 3.8 kg.

Medication

Patient was receiving steroids and sulfasalazine intermittently.

For portal hypertension she is also receiving furosemide and spironolactone

Vitamin D supplements are also given

Examination

Height (114cm) for age: <3rd percentile

Weight 35 kg

Breasts well developed – Tanner IV,

No armpit hair growth, parse pubic hair – Tanner II

Laboratory Investigations

Other Investigations

Histology (Colonoscopy)

The other proposed additional examination is a pubic ultrasound to evaluate the ovaries, fallopian tubes and uterus.

It was also proposed that IGF binding protein 3 be measured, as low levels may yield IGF-1 shorter biologically active.

Final Diagnosis

Primary amenorrhoea most likely due to a physiological delay. Although the pelvic ultrasound hasn’t been done at the time of writing, the low IGF-1 likely indicates a low growth due to chronic systemic disease – see other possible aetiologies below.

Take Home Message

Amenorrhea can be a condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina.

The most common aetiologies include:

• Gonadal dysgenesis, including Turner syndrome – 43%
• Müllerian agenesis (absence of vagina, sometimes with absence of uterus) – 15%
• Physiological delay of puberty (constitutional delay of puberty, chronic systemic disease, acute illness) – 14%
• Polycystic ovary syndrome (PCOS) – 7%
• Isolated gonadotropin-releasing hormone (GnRH) deficiency – 5% (possible selection bias)
• Transverse vaginal septum – 3%
• Weight loss/anorexia nervosa – 2%
• Hypopituitarism – 2%

Abnormal Result

Prolactin >1000 ug/L

Presenting Complaint

Patient presented at 7 years of age with galactorrhea and visual field defects.

History

Patient had a craniotomy for debulking of the adenoma. This was opposed to the usual transsphenoidal more non-invasive route of pituitary adenoma surgery. She was initiated on Cabergoline 1 g twice weekly for suppression of the tumour size.

It was also noted during surgery that the tumour was extremely vascular with much bleeding and the neurosurgeons struggled to mobilize it to adequately get it separated from the optic chiasm. Some portion of the tumour was left in situ during surgery as this was too big a risk for trying to excise.

A biopsy was also taken.

Examination

Patient subsequently developed severe intracranial edema after surgery in the ICU.

Laboratory Investigations

Other Investigations

Histology

Frozen section – pituitary adenoma. GROSS DESCRIPTION: Specimen labelled tumour. Specimen consists of 2 fragments of tissue, larger measuring 4x3mm. HISTOLOGY: Sections show tumour tissue composed of nests of monotonous cells with intervening fibrous septae. The cells have round nuclei and abundant eosinophilic cytoplasm. The nuclei have stippled chromatin with inconspicuous nucleoli. No mitotic activity or necrosis is seen. Immunohistochemistry: Synaptophysin:Positive Prolactin: Positive LH: Negative FSH: Negative GH: Negative TSH: Negative ACTH: Negative CONCLUSION: Pituitary, mass, excision: – Pituitary adenoma with an immunohistochemical profile compatible with a prolactinoma.

Final Diagnosis

Pituitary Macroadenoma

Take Home Message

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson’s disease, and for other indications. It is taken by mouth. Cabergoline is an ergot derivative and a potent dopamine D₂ receptor agonist.

Lactotroph adenomas (prolactinomas) are more amenable to pharmacologic treatment than any other kind of pituitary adenoma because of the availability of dopamine agonists, which usually decrease both the secretion and size of these tumors. For the minority of lactotroph adenomas that do not respond to dopamine agonists, other treatments must be used. Hyperprolactinemia due to nonadenoma causes should also be treated if it causes hypogonadism.

There are two principal reasons why patients with hyperprolactinemia may need to be treated: existing or impending neurologic symptoms due to the large size of a lactotroph adenoma, and hypogonadism or other symptoms due to hyperprolactinemia, such as galactorrhea.

A third indication is in women with mild hyperprolactinemia and normal cycles who are trying to conceive as they may have subtle luteal phase dysfunction.

Abnormal Result

Upon authorizing blood results I came across a aldosterone result of 23300 pmol/L.

After a moment of brief anxiety, luckily I realized this was part of a series of tests performed by my colleagues in the Department.

Presenting Complaint

Medical complaint: Suspected Conn’s disease – right adrenal lesion/ irregular left adrenal gland.

History

The patient was confirmed to have primary hyperaldosteronism.

Unfortunately more information is not known. We were asked to assist with the sampling and the whole history weren’t available.

Examination

Not available

Laboratory Investigations

Other Investigations

Not available for this patient.

Ideally one would need a CT with contrast beforehand to adequately visualize the positions of the adrenal veins, as this may aid in the canulation, especially of the right adrenal vein.

One needs to diagnose hyperaldosteronism (by an appropriate salt loading test) before proceeding to bilateral adrenal vein sampling.

Final Diagnosis

Interpretation

Selectivity index

Right: 1.0 (mean)

Left: 19.0 (mean)

These two results indicate that the left adrenal has been canulated adequately, but the right vein inadequately.

Lateralization index

Unable to comment because of the inadequate canulation of the right adrenal vein. If determined, it would very likely provide a false result.

Contralateral suppression index

1.5 : 1.8 = 0.8

This falls in between some of the referenced cutoffs (<1 and <0.5)

All of the other samples also fall somewhere in this range. Biochemically, these results suggests inadequate right sided venous sampling (a commonly described problem)

Take Home Message

• Procedure is done in the Cath Lab
• The patient received continuous synacthen infusion – as this improves the sensitivity (or perhaps rather specificity) of the test.
• Done under imaging with contrast used for the localisation of the adrenal gland and adrenal vein
• Sequential sampling technique used, generally > 20 mins infusion
• Multi-disciplinary: nurses, anaesthetist, radiographer, intervention radiologists, students, chemical pathologists
• Difficulty with sampling right side for both patients
• Difficulty with interpreting results – most likely due to inadequate canulation of the right adrenal vein

Some important learning points

1. Adrenal vein sampling may be a valuable tool that is underutilised
2. Careful selection of patients essential – also patient should consent to surgical removal of the affected adrenal before this invasive procedure is initiated
3. Inter-disciplinary approach is necessary
4. Obtaining cosyntroponin (aka synacthen) can be difficult (Section 21), but recommended.
5. Right adrenal access difficult: may require specific imaging. Recommended to start on the right or do simulataneous sampling.
6. Adrenalectomy may be curative or help achieve better control of BP thus decrease associated morbidity and mortality in those with unilateral adenoma

Abnormal Result

Potassium of 1.9 mmol/L was found on a blood gas analysis.

Presenting Complaint

Patient presented with a few isolated episodes of muscle weakness. This progressed from 2 weeks before, during the index episode, to become so severe that he couldn’t walk.

History

Patient was given IV potassium + MgSO4 upon which the potassium normalised to 5.5 mmol/L
History of muscle weakness was on and off over the last few months – unable to walk for brief periods of time.
No Family Hx of illnesses / hypokalmeia
No hypertension and no family Hx of hypertension
Patient had sweating more than usual. No other overt Sx of hyperthyroidism.
No medications

The mother had no similar symptoms ever.

The father was unfortunately not involved and not contactable.

Examination

Normal pulses
Small goiter, diffusely enlarger
No cardiovascular system abnormalities

Laboratory Investigations

Potassium upon the current consultation: 4.6 mmol/L
Normal Sodium, Creatinine, calcium, magnesium, phosphate and chloride

Normal pH 7.35
Normal HC03
Suspecting: Hypokalemic periodic paralysis
TSH < 0.01
Free T4: 59 pmol/L
Free T3: 21 pmol/L
TSH-Receptor Antibodies: Increased above the cut-off

Creatine Kinase 749

Other Investigations

The further investigations needed to confirm the diagnosis

Final Diagnosis

Considering the fact that the patient had no renal tubular acidosis, no medication which could cause the low potassium, it was, according to the endocrinologist, likely a diagnosis of Thyrotoxic Periodic Paralysis (TPP).

Patient was placed on Neomercazole and a Beta-adrenergic receptor blocker.

Take Home Message

I wasn’t aware of the condition until this case was brought up to the endocrinology meeting.

Thyrotoxic periodic paralysis is a rare cause of muscle paralysis.

TPP is a disorder most commonly seen in Asian men, is characterized by abrupt onset of hypokalemia and paralysis. The condition primarily affects the lower extremities and is secondary to thyrotoxicosis.

It has been increasingly reported in the USA due to the rise in the immigrant population. Hypokalemia in TPP results from an intracellular shift of potassium induced by the thyroid hormone sensitization of Na⁺/K⁺–ATPase rather than depletion of total body potassium. Treatment of TPP includes prevention of this shift of potassium by using nonselective beta-blockade, correcting the underlying hyperthyroid state, and replacing potassium.

It is important for physicians to distinguish TPP from familial hypokalemic periodic paralysis, a more common cause of periodic paralysis in Caucasians. The absence of a family history of paralysis, male sex, presentation in the second to fourth decades of life, and signs of thyrotoxicosis like sinus tachycardia help in the diagnosis of this disorder. Early recognition of TPP is vital to initiating appropriate treatment and to avoiding the risk of rebound hyperkalemia that may occur if high-dose potassium replacement is given.

It is most common in Asian populations – incidence approximately 2% in patients with thyrotoxicosis of any cause.

It has been recognized in Thais, Filipinos, Vietnamese, Koreans, Malaysians, Hispanics, African Americans, and Caucasians. It is characterized by acute onset of severe hypokalemia and profound proximal muscle weakness in patients with thyrotoxicosis.

Abnormal Result

49yr old female

Presenting Complaint

Medical complaint: Suspected Conn’s disease – right adrenal lesion/ irregular left adrenal gland

History

Past Medical History: Resistant Hypertension, primary hyperaldosteronism (confirmed previously with saline infusion test), hypokalaemia, hypercholesterolaemia, newly diagnosed DM.

Family History: Hypertension – Mother.

Past Surgical History: TAH – 7 years ago.

Allergies: Nil known

Smoker

Meds: Amlodipine/Valsartan 10/320 daily, Doxazosin 8mg daily, Furosemide 40mg daily, Spironolactone 25mg daily, Carvedilol 25mg daily, Metformin 1g nocte, Simvastatin 20mg nocte, Zolpidem 10mg nocte.

Examination

Not available

Laboratory Investigations

Other Investigations

Not available for this patient.

Ideally one would need a CT with contrast beforehand to adequately visualize the positions of the adrenal veins, as this may aid in the canulation, especially of the right adrenal vein.

One needs to diagnose hyperaldosteronism (by an appropriate salt loading test) before proceeding to bilateral adrenal vein sampling.

Final Diagnosis

Interpretation

Selectivity index

Right: 0.2 (mean)

Left: 2.8 (mean)

These two results indicate that the left adrenal has likely been canulated adequately, but the right vein inadequately.

Lateralization index

Unable to comment because of the inadequate canulation of the right adrenal vein. If determined, it would very likely provide a false result.

Contralateral suppression index

616.8 /1260.25 : 2540/3609

= 0.70

This falls in between some of the referenced cutoffs (<1 and <0.5)

All of the other samples also fall somewhere in this range. Biochemically, these results suggests inadequate right sided venous sampling (a commonly described problem)

Take Home Message

• Procedure is done in the Cath Lab
• The patient received continuous synacthen infusion
• Done under imaging with contrast used for the localisation of the adrenal gland and adrenal vein
• Sequential sampling technique used, generally > 20 mins infusion
• Multi-disciplinary: nurses, anaesthetist, radiographer, intervention radiologists, students, chemical pathologists
• Difficulty with sampling right side for both patients
• Difficulty with interpreting results – most likely due to inadequate canulation of the right adrenal vein

Some important learning points

1. Adrenal vein sampling may be a valuable tool that is underutilised
2. Careful selection of patients essential – also patient should consent to surgical removal of the affected adrenal before this invasive procedure is initiated
3. Inter-disciplinary approach is necessary
4. Obtaining cosyntroponin (aka synacthen) can be difficult (Section 21), but recommended
5. Right adrenal access difficult: may require specific imaging. Recommended to start on the right or do simulataneous sampling
6. Adrenalectomy may be curative or help achieve better control of BP thus decrease associated morbidity and mortality in those with unilateral adenoma

Abnormal Result

TSH: < 0.01 mIU/L (0.27 – 4.2)

Free-T4: 80.9 pmol/L (12 -22)

Free-T3: 10.8 pmol/L (3.1 – 6.8)

Presenting Complaint

Started to have frequent supra-ventricular arythmias – hence placed on amiodarone by the cardiologists

History

Mitral valve repair in 2018.

Started Warfarin, then later stopped.

Upon routine visit for follow-up 1 w before, the cardiologist requested TFT’s.

Examination

• Denies chest pain, shortness of breath and has no symptoms of dyspnoea
• No lower limb oedema
• No sweating
• No abdominal complaints
• Patient is comfortable, no distress
• CVS unremarkable
• Muffled systolic murmur, JVP normal, No lower limb oedema.
• Fine tremor, pulse rate 84
• No eye signs
• Gland diffusely enlarged, and no focal nodules detected
• Bruit was clearly audible

Laboratory Investigations

TSH receptor antibodies = 3.3 U/L (<1.8)

Other Investigations

Radio-active Iodine thyroid uptake scan showed no uptake in the thyroid gland – not indicative of Graves Thyrotoxicosis.

Final Diagnosis

Summary: 21 y female, 1 y after mitral valve replacement placed on amiodarone now presented with a diffusely enlarged thyroid gland with a bruit clearly audible and no signs or symptoms of hyperthyroidism, but with biochemical evidence of significant hyperthyroidism

DDx: No symptoms pointing towards overt thyroid problems before initiating, thus this is likely Amiodarone – induced thyrotoxicosis

2 types are known, differentiated by either a diffusely enlarged thyroid which is more likely type 2 than type 1 .

Take Home Message

Rx differs between type 1 and type 2:

High iodine uptake is usually type 1 : usual Rx of Hyperthyroidism is given, thus Lugol’s iodine, else if non-responsive: radio-active Iodine or surgery.

If not much uptake on the uptake scan: Type 2 : points towards destruction of the gland : Rx = steroids

Which is more common?

In a local study of ~250 patients in 10y period it was found the longer it is left, the higher the chance of thyrotoxicosis. “Type 2 is likely more common”- prof Ross.

How does lithium thyroid disease work?

Lithium increases the enterothyroidal iodine recirculation : characteristically causing a : goiter with hypo or hyperthyroidism (thyroiditis).

Lithium inhibits proteases which liberates T3 and T4, hence inhibiting Iodine recirculation.

Interestingly, despite having a free T4 of ~80pmol/L, the patient had no symptoms whatsoever.

Also, of note, amiodarone more often causes hyperthyroidism than hypothyroidism.