Chapter 4: Endocrine tales

It would indeed be rash for a mere pathologist to venture forth on the uncharted sea of the endocrines, strewn as it is with the wrecks of shattered hypotheses, where even the most wary mariner may easily lose his way as he seeks to steer his bark amid the glandular temptations whose siren voices have proved the downfall of many who have gone before.

William Boyd (1885–1969)

This classic cautionary case about a 16-year-old Western Australian female student serves as a reminder that any of us could be misled by the capricious Addison’s disease. She presented to her general practitioner with four weeks of fatigue and tiredness. Her mother reported that she suffered from malaise and anorexia and had lost weight and seemed prone to ‘pick up any bugs that were going around’. There was no significant past history although she was reportedly diagnosed as having glandular fever six months previously. Physical examination was normal. A series of blood tests including a full blood examination was ordered and reported as normal.

Over the next four to five months the patient continued to feel unwell and stopped attending school because she felt so tired and lacked energy for her usual activities including sport. Other reported problems included poor concentration, somnolence, continued loss of weight, anorexia, vomiting (up to five times a week) and syncope during venesection followed by prolonged dizziness. She had several consultations with different practitioners including a mental health assessment but was still without a firm diagnosis. Physical examinations were recorded as ‘unremarkable’ despite a discussion, probably initiated by her father, about skin colour changes.

During her final blood test at the GP’s clinic she fainted and remained too dizzy to return home and was referred to the local hospital for resuscitation with intravenous fluids. Back at home she remained unwell but refused her parents’ wish to attend for review of her blood tests. Her parents were in the process of taking the by now rather cachexic girl to hospital when she was found dead in bed. The post-mortem examination concluded that the cause of death was adrenal insufficiency due to autoimmune destruction of the adrenal cortex. (Bird, 2007a.)

MORE MEDICAL BRAIN TEASERS

• I recall seeing a 7-year-old boy in the emergency department of the Children’s Hospital referred from a physician in a provincial city because of two months of dizzy spells and blackouts. I performed a routine blood sugar and found hypoglycaemia. The penny dropped. I went looking for and found hyperpigmentation in the oral mucosa.

• Recently I received an email from a British GP saying that it took two and a half years for her Addison’s disease to be diagnosed. Another member of the UK Addison’s Disease Self Help Group waited 15 years to be diagnosed after treatment for depression and chronic fatigue syndrome. A 9-year-old child with asthma from three years of age was eventually diagnosed with secondary Addison’s disease after ten hospital admissions in five years for recurrent vomiting and diarrhoea. The writer was sympathetic to the difficulty of diagnosis and pointed out that the single blood tests were unreliable. ‘Highlight it in your books’ was the message.

• A friend developed diarrhoea during a stressful trip to Nepal (having accidents and being robbed). Two weeks of lethargy, anorexia, nausea, vomiting, diarrhoea and abdominal pain followed. She was then treated with Flagyl for presumed giardiasis. After collapsing at home, she was admitted to hospital confused, febrile and hypotensive. Four days after being discharged to home, she collapsed again and was readmitted to hospital semi-conscious. This was diagnosed as an Addisonian crisis. Her eventual outcome has been good.

Gladys is a delightful 81-year-old lady, who has been attending for the past 12 years with angina pectoris and mild congestive cardiac failure. The latter had been well controlled with the daily administration of digoxin 0.125 mg, chlorothiazide 0.5 g and potassium chloride 1200 mg. She was taking glyceryl trinitrate (nitroglycerin) for her angina.

Ten months ago she presented with increasing dyspnoea on exertion, weakness and nocturia. The diagnosis of poorly controlled congestive cardiac failure was made, and frusemide 80 mg with increased potassium was added to her daily regimen. The serum digoxin level ordered at this visit was normal.

She improved slowly but on review was still weak and short of breath. I noticed that she was pale and frail but otherwise appeared normal for her age. The results of further blood tests were as follows:

In view of her age I rationalised that as her anaemia was mild no further investigations were warranted. Furthermore, I considered that no likely treatable cause would be found. I placed her on isosorbide nitrate, iron tablets and multivitamins with a reassurance that she would cope nicely if she took ‘things easy’.

DIAGNOSIS

During my holiday leave Gladys presented with a severe episode of angina, and she was treated by my Family Medicine Programme trainee who decided to investigate her problem further. He ordered thyroid function tests, blood glucose, urea and electrolytes. Upon my return the pathology slip waiting in my pigeon hole read as follows:

serum thyroxine 19 (N: 65–165 n mol/L)

serum T3 uptake 31 (N: 35–45 per cent)

serum free thyroxine index 6 (N: 21–66)

serum TSH 91.9 (N: 0.0–5.0 uU/mL)

She was hypothyroid, thus providing the answer for her normochromic anaemia and her medical dysequilibrium. This fact was not clinically obvious to us.

The words ‘missing links’ may bring to mind thoughts on evolution, apes, near-humans and the origin of the species. But in day-to-day medical practice missing links can be the cause of significant and serious medical conditions. These links, or factors, when discovered and put back into place will bring about the reversal of all, or most, ill effects caused by the absence of that vital link and make a sick person healthy.

The effects and changes caused by the missing factors may be insidious, may take a long time to reveal obvious clinical signs, are easily missed and often embarrass the unwary observer. The resulting conditions may come to light in people that you know well and see frequently, and who have complete faith in your capabilities and clinical acumen.

Now the stories unfold …

MRS S

Mrs S, in her fifties, had not had a comfortable life. She had nine children, not all of them easy to manage, and had become a grandmother at an early age with added caring responsibilities. Her husband had always been a heavy drinker and at an early age developed Parkinson’s disease, with total incapacity.

Understandably, I thought, she always seemed to be tired, to have difficulty with weight and to be depressed. Because of her various involvements, I saw Mrs S frequently and sympathised with her feelings and predicament. I failed to notice that she felt the cold easily, and that her voice was getting deeper and her hair coarser. It was not until I noticed her change in features from Mrs Jekyll to Mrs Hyde that the penny dropped. Appropriate investigations and correct treatment quickly followed. The thyroxine worked like magic, and we saw the return of the Mrs S we all used to know. Myxoedema can trap even the experienced observer.

On a visit to Mrs S several months later I thought her features were a bit coarse, and she said she had been having weight problems again. A check on her thyroid function tests showed that her thyroid needs had increased. Be ever watchful.

LAURA

Sometimes the illness caused by the missing link can be life threatening, suddenly and dramatically.

Laura was a pretty 13-year-old, full of energy and a strong tennis player. She was one of three children in a happy family. Her brother, three years older, had been blind from birth and had become epileptic at an early age. Laura presented on a Monday afternoon with persistent vomiting, and as there was a lot of vomiting of viral aetiology in children of the district she was diagnosed as having viral gastroenteritis. Her condition did not improve and I saw her on Friday of that same week. As we went carefully over the history I could not help but notice that Laura was falling asleep upright in the chair, ready to topple over.

‘How long has she been like this?’

‘Only today.’

‘Has she been passing much urine?’

‘She never seems to stop.’

‘Before the vomiting episode, was she drinking a lot?’

‘We kept running out of soft drink, cordial and fruit juice.’

‘Had she been well?’

‘She’s been very tired—she couldn’t even be bothered with her beloved tennis.’

A quick blood sugar showed a sky-high level; a ketotic Laura was admitted to hospital that afternoon. By Monday morning she was back home, well and self-injecting with insulin twice daily. She was her old self, having accepted her missing link philosophically.

As we know, when the particular factor or link goes missing in such cases as myxoedema, diabetes mellitus, pernicious anaemia and Addison’s disease, we have a serious, life-threatening, often insidious disease evolving. The recognition of the missing link and its immediate replacement will bring about a miraculous recovery that has the patient saying, ‘Doctor, I’ve never felt better in my life’.

Mrs Leyma K, a recently arrived Latvian immigrant, presented with an English-speaking cousin. Leyma could not communicate in English at all. Her cousin said that she wanted Leyma to have a good check-up and would like her to be referred to a multiphasic screening centre. Leyma had felt uncharacteristically nervous and irritable since her arrival in Australia four months ago.

Leyma had visited a Latvian-speaking doctor who was very abrupt with her and prescribed a benzodiazepine for an anxiety state, but apparently she felt worse on the tranquiliser.

I was rushed and so I took a brief history via the interpreter, who said that Leyma was feeling stressed and upset about leaving her native country and was finding the heat of the Australian summer unbearable. I wrote out a referral to the screening centre.

Two weeks later I received a most impressive and expensive computer print-out with one abnormal test among the hundreds. Her thyroid function tests showed marked hyperthyroidism. The diagnosis had been staring me in the face: thin, anxious, sweaty, tachycardiac and intolerant to heat although no eye signs.

During the full fury of the Pacific War in 1943 the army discharged Eddie Murphy, a 32-year-old soldier, back to the care of his general practitioner. Apparently Eddie had become sick during action; he felt very irritable, nervous and weak, and was hospitalised for four months with a short spell in the ‘bomb happy’ ward.

Eddie’s problem baffled the doctors, including a panel of three consultants who detected an abnormality with his heart rhythm. They concluded eventually that Eddie’s problem was functional and gave him an honourable discharge with the diagnosis of ‘disordered action of the heart’.

His GP was amazed to find that Eddie looked ill, was rather agitated and had lost weight. When he shook Eddie’s hand and instinctively felt his pulse, the diagnosis was obvious.

DIAGNOSIS AND OUTCOME

Eddie had thyrotoxicosis—rather classic apart from the lack of exophthalmos. His warm sweaty palms and atrial fibrillation were very significant. However, in making this diagnosis his GP enjoyed the distinct advantage of already having treated two members of his family with the same problem. Fortunately, Eddie responded nicely to a prolonged course of iodine in milk and spent the duration of the war in ‘active service’ on his farm.

One Sunday morning a person rang urgently to say that her 78-year-old mother-in-law, Mrs Williams, who had arrived to stay, was very ill. ‘Would you please call, Doctor’, she said. I initially baulked at the prospect, because the caller had moved out of my area to a suburb some 8 km away. The elderly patient’s doctor, whose surgery was only 5 km away, refused to call because it was outside his 2 km ‘call limit’.

However, I continued to listen. ‘It is not possible to arouse mother for breakfast. She is in a coma, Doctor. She was discharged from hospital yesterday after convalescing from a total hip replacement. She has had a wound infection but she seemed quite well last night. She has a bottle with some Serepax in it by her bed.’

The mind started racing. ‘Why should I go? An overdose—great! I’ll call an ambulance. No, I’ll get her doctor to go—no, I’ll call her surgeon.’ These escapist thoughts were interrupted by a persuasive interjection, ‘Could you please help us—we don’t know what to do’.

‘Damn—I’ll go’, I thought. ‘It’s probably a cerebrovascular accident (CVA) anyway or septicaemia. Myocardial infarction? Pulmonary embolus? No, most likely an overdose—the lady’s depressed or confused.’

With the adrenaline running high, I arrived at the house. The anxious relatives looked relieved. I was led into a cold, damp room to find a semiconscious elderly woman lying in bed. She would respond to painful stimuli by throwing her arms about and moaning. There were no neurological abnormalities on physical examination. Temperature was 36.5 ?C (per axilla), pulse 86/min, respiration 16/min, blood pressure 160/90. What could the problem be?

I could not really tell if she had overdosed on Serepax. I searched and found a bottle of glibenclamide (Daonil) tablets in her handbag.

‘Could she have hypoglycaemia? Well probably not—that’s usually caused by insulin’, I thought.

In my doctor’s bag, I found a bottle of Dextrostix. Two months beyond expiry date. I wished I had my glucometer with me. However, I took some blood from her fingertip (provoking a response) and tested it—3 mmol/L.

Now to impress everyone! I checked for a suitable vein (which was present), seized a vial of 50 per cent Dextrose solution, drew the contents into a 20 mL syringe and injected the rather cumbersome solution. Within a minute the real Mrs Williams awoke and looked around the room bemused, especially at the stranger who stood over her looking pleased.

I was certainly glad I went on that house call. I love diagnosing and treating hypoglycaemic attacks. It’s one of the few times a general practitioner feels really powerful and satisfied.

It brought back recent memories of being called to Cyril, an old insulin-dependent diabetic, who was found unconscious on the floor of the local supermarket. The curious crowd thought he was stone dead and he certainly looked it. Imagine the reaction when this ‘corpse’ sat up as large as life when ‘the treacle’ was injected by the apparently calm, all-knowing GP. Even the anti-doctor critics were impressed.

Mrs Fraser, a farmer’s wife, came to me with a minor ailment not long after she moved with her husband and two children to the district. She brought with her a letter, written by their previous family doctor in South Australia, which informed me that her husband was an insulin-dependent diabetic.

Shortly after harvest Mr Fraser came in to renew his insulin prescription. Tall, slim, tanned and seemingly very healthy, he was a pleasant man and well educated in the management and possible complications of his disease. Most of our consultation was devoted to discussion of general topics. His file already had been marked ‘diabetic’ and I looked forward to having little to do for him except write his insulin prescriptions. (The days of glycosylated haemoglobin and glucometers were yet to come.)

Four months later he consulted me for the second and last time. He said he had felt ‘off colour’ for two or three months and so had been taking some of his wife’s iron tablets left over from her last pregnancy. Now he felt generally unwell and noticed his ankles were swollen.

Examination revealed that he was in cardiac failure. Then the penny dropped: his tan was not a healthy suntan but bronzing. He had haemochromatosis, a rarity but something that should have occurred to me when I first saw him.

My preconception that he had diabetes was a misconception.

Harold, a 57-year-old builder, had been a patient of mine for 25 years. He had a history of peripheral neuropathy of unknown cause, controlled by exchange transfusion with immunoglobulin. In 1962 he acquired syphilis with no apparent sequelae. He smoked 30 cigarettes per day and was a teetotaller.

In August 1990, a random glucose was 5 mmol/L but in September 1991, when a blood lipid profile was ordered, a random glucose was 10 mmol/L, while random cholesterol was only 3.7 mmol/L and triglycerides was 5.9 mmol/L.

A fasting glucose, which was then ordered, was 6 mmol/L. Although these figures did not satisfy the criteria for diagnosis of diabetes (7 mmol/L fasting or 11 mmol/L random), I was suspicious about the possibility and ordered a glucose tolerance test.

This showed a fasting glucose of 20, a 1 hour of 32.5 and 2 hour 35 mmol/L. Insulin was 13, 11 and 17 units respectively. All insulins were within the normal range.

He was diagnosed as a non-insulin-dependent diabetic. He was started on a diet with the help of a diabetic educator and his blood sugar level (BSL) was monitored.

He was most cooperative, and his weight decreased from 72 kg to 59 kg and his BSL remained constantly in the normal range.

ABDOMINAL MASS

In May 1992 he noticed a lump in his abdomen. Examination disclosed a pulsating lump and a CT scan showed a small abdominal aortic aneurysm.

The CT, which was repeated in September 1992, showed no changes in the size of the aneurysm and no other abnormality in the abdominal organs. Harold continued to lose weight and although this was a concern to me it was attributed to his zealous dieting.

His height was 171.5 cm and with a weight of 59 kg that represents a body mass index of 20, just inside the normal of 20 to 25.

In November 1992 he complained of right upper quadrant abdominal pain. He was tender but not jaundiced. Liver function tests showed normal bilirubin and alkaline phosphatase but the AST (aspirate transaminase) (formerly SGOT) was slightly raised at 75 units (normal, 60).

The pain and tenderness settled without treatment while a follow up AST was 2 units.

Harold requested a repeat CT of his abdomen in January 1993.

The CT was reported as follows: ‘In the scans throughout the upper abdomen there are multiple low-density lesions present in the liver, the appearance suggests metastatic disease. The head of the pancreas appears a little irregular, the appearance is not marked but in view of the liver findings a carcinoma would have to be considered’.

At laparotomy there was a firm hard mass in the head of the pancreas with multiple liver secondaries.

Harold died in May 1993.

A 34-year-old housewife with insulin-dependent diabetes (IDDM) since the age of 14 presented with a 3-day history of sore throat, nausea, vomiting and chest pain radiating to the shoulder. The patient was not eating and was advised to stop taking insulin. Antibiotics were prescribed for the throat infection.

Twenty-four hours later her condition had deteriorated with persistent nausea and vomiting; in addition she was very thirsty and had polyuria. She was sent to the emergency department of a large city hospital for investigation and management.

On examination, the patient was conscious but dehydrated. Her vital signs were blood pressure 110/60, respiration 22 per minute, pulse 110 per minute, temperature 36.5?C. Urinalysis showed 110 mg glucose and large amounts of ketones. Her throat was inflamed, but there was no lmphadenopathy. A chest X-ray was normal. The provisional diagnosis was diabetic ketoacidosis.

BIOCHEMISTRY

The results of serum analysis showed glucose 45 mmol/L, pH 7.24, HCO₃ 11 mmol/L, Na 128 mmol/L, PO₂ 110 mm Hg and PCO₂ 26 mm Hg, K+ 5.3 mmol/L, urea 8.3 mmol/L, creatinine 13 mmol/L.

MANAGEMENT AND OUTCOME

Intravenous normal saline was commenced to correct the dehydration at the rate of 1 litre over 2 hours. Insulin was given by intravenous infusion––100 units of short-acting insulin (Actrapid) in 500 mL of Haemacel. The infusion rate was regulated on a sliding scale according to blood glucose levels obtained by fingerpricks, following a loading dose of 6 units of Actrapid, with the aim of slowly lowering the blood glucose to 7 to 10 mmol/L.

Potassium (K+) replacement was given once urine output was established to maintain a level between 4 and 5 mmol/L. Intravenous fluid was changed to 4 per cent dextrose in ⅕ NS when her blood glucose was 12 mmol/L and ceased in 24 hours––after symptoms settled and the patient was eating and drinking.

The patient was discharged five days after admission on her usual dose of insulin: Actrapid HM 8 units morning, 4 units evening and Protophane HM 18 units morning, 4 units evening. Diabetes education and management of sick days were reviewed during admission.

I inherited the miserable Olive M, a 73-year-old mother of ten children, from my predecessor when I entered country practice. The diagnosis on the white card read ‘generally worn out and depressed’ and she was prescribed a tonic and thyroid extract, after a failed trial of ‘purple hearts’.

Olive, who looked old, thin and depressed, would shuffle into the consulting room saying, ‘I’m still a bag of misery, Doctor, I ache all over, my legs ache and ache especially the shins, my back aches, I’ve no energy and I can’t eat, but the worst thing is this constipation. I get bound up and it causes gripes in my stomach. What’s the point of going on like this?’

Medical school had not prepared me for this—I had heard all about ‘undifferentiated illness’ in general practice. There was no doubt she was depressed. Previous investigation showed normal thyroid function, full blood examination and many other tests including serum electrolytes. The only abnormality was in renal function with mildly elevated serum urea and creatinine but not in the renal failure range. Apart from a BP of 180/95 there was absolutely nothing abnormal to find on the physical examination.

I stopped the thyroid extract and prescribed antidepressants. When I followed up with a house call, I found her in bed behaving irrationally and complaining of generalised itching. She was psychotic and she kept saying that she ‘was ready to meet the Lord’. I then admitted her to hospital.

DIAGNOSIS AND OUTCOME

When I arrived for my usual evening rounds I found the priest giving her the last rites. The family had all assembled. One of the sons who had some peripheral medical knowledge had decided Mum was dying and her death was imminent, despite my prognostications that this was not so and that ‘we would get to the bottom of it’.

In frustration I decided to ring a colleague who had just passed his physician’s exams and was an excellent diagnostician, especially with the rare and obscure. After listening to the history Roger said it all with just a few well-chosen words: ‘John, moans, bones and abdominal groans––remember? Any stones?’ Within a few weeks Olive had her parathyroid adenoma removed by a skilled neck surgeon in Melbourne. The transformation was incredible. A normal, happy, energetic and wonderful woman would see me and tell me how clever I was. I informed her that if I had been clever I would have saved her three months of moans, bones, abdominal groans, constipation and humiliation.

Olive died 12 years later. As the priest with his delightful Irish wit said, ‘Can’t beat the last rites, works wonders!’

‘Did you see cousin Mike at the family funeral?’

‘No, I didn’t see him.’

‘Well you wouldn’t recognise him. He looks strange, as though there’s something wrong with his glands’, came the layperson’s reply.

Then I recalled seeing a fellow who looked acromegalic. Further inquiries revealed that the acromegalic-looking ‘stranger’ at the funeral was indeed the unrecognisable Mike, a 38-year-old teacher.

A phone call to his concerned mother determined that Mike had been unwell for seven years, but at the moment was having radiological investigation through his general practitioner who, at last, had heard a ‘penny drop’. The saga for Mike was remarkable. For the past seven years his mother had observed him becoming ‘bigger and uglier’. He was noticed to become very tired, irritable and sweaty.

A discussion with Mike produced a very interesting version. The first thing he noticed was broadening and enlarging of his nose, which was subject to two operations by an ENT surgeon. Over a period of six years he noticed also the following symptoms and signs that developed slowly:

• clothing became tighter, especially shirts with buttons

• hands increased in size and became thicker

• ‘pimples’ (almost like boils) appeared on his back

• snoring started, which became ‘gross’

• ski gloves would no longer fit his hands

• feet became broader and thicker, and shoe size increased

• chest became so enlarged that people thought he was a weight-lifter, and the sternum became very pronounced

• eyes appeared sunken as face, eyebrows, lips and nose enlarged

• speech changed with slurring of words because the tongue would ‘no longer fit my mouth cavity—it was larger than my bite’

• lower jaw moved forward and ‘my bite was faulty’

• there was a tendency to persistent colds and influenza

• skin became very sweaty—’I was hot and clammy to touch’

• thirst became excessive

• urine was a dark colour and had a pungent smell

• body hair and ‘beard’ became thinner

• sex drive reduced but ‘performance was normal’

• weight gain was 18 kg but no fat, all ‘bulk and muscle’.

Two years previously Mike developed severe lower back pain and visited a chiropractor who felt that he had acromegaly and should report to his family doctor. Amazingly, his doctor dismissed this diagnosis and did not in fact consider the diagnosis during several other visits. Eventually, the doctor did consider it and ordered scans, which detected a very large pituitary tumour.

OUTCOME

Mike had surgical removal of his pituitary tumour followed by bromocriptine medication. He feels considerably better, but there has been only minimal reversal of his appearance.

The ‘elephant man’ feeling

The biggest disappointment to Mike was the attitude of his specialist attendants in hospital. He said: ‘I felt like a plate of meat—not a person. I really felt like the elephant man. Dr––– would come into my hospital room with his entourage and, without asking permission, say with great glee, “Look at this classic case of acromegaly—look at his chest, feel his clammy skin, look at his feet” and so on. There were no explanations about the cause of the tumour or follow-up instructions, and I’m a university graduate.’

Mr JT is a 44-year-old tradesman who had been very fit and rarely attended any doctor. He presented to me complaining of an occipital headache. A full neurological examination was normal. His blood pressure was 120/80. I considered that a viral headache was the most likely cause and treated him with simple analgesia and rest.

The next night I was called to visit him as he had developed a severe pounding headache while straining on the toilet. Neurological examination was again normal, but his blood pressure was elevated at 210/80. He was referred to a major public hospital for further assessment.

When I saw him the next day he had undergone a CT scan of his brain, which had proved normal.

Three days later I was called to see him as he had once again developed a severe headache associated with vomiting. Due to the persistence of his headache he was referred back to the public hospital for further assessment. He returned home following a lumbar puncture, which proved normal.

My fourth visit revealed him to have a slight headache and his blood pressure was still elevated at 150/100. Due to the persistence of his hypertension I decided to commence him on felodipine 5 mg daily and order blood urea and electrolytes, which were normal.

JT’s blood pressure was well controlled on the felodipine, but I remained suspicious that an undiscovered cause prompted his sudden presentation. I undertook a series of 24-hour urinary catecholamines, especially as he complained of recent occasional palpitations and sweating. To my surprise the series of 3 × 24-hour urinary catch catecholamines strongly suggested the possibility of a phaeochromocytoma (see table below).

Because of these results I ordered a CT scan of his abdomen. This revealed a right-sided adrenal tumour diagnosed as a phaeochromocytoma, which measured about 5 cm in diameter, and had a zone of necrosis laterally (Figure 4.3).

Back in hospital, he underwent a right adrenalectomy under cover with α and β blockage. At operation the right adrenal was found to have been replaced by an encapsulated soft, partly yellow, partly brown mass. There was no evidence of metastatic spread. He made a good recovery and his blood pressure remains normal.

The symptoms described were all present in my patient and could be eliminated with further accurate questioning.