This 50 year old female was admitted to a hospital with the following Chief Complaints:
- Back pain
- Muscle Weakness
After 6 days she developed Fatigue and Loss of Appetite. After a further 2 days, she was becoming increasingly weak and could not get out of bed. Her husband needed to help her get to the toilet, and on one occasion she experienced diarrhoea.
At this point, several important questions were asked to elaborate on the history such as what type of fever was it? Continuous or Oscillating / Spiking Fever. The latter is very suggestive of a bacterial / viral infection / abscess whereas continuous low grade fevers can represent non-infective aetiologies once infection has been ruled out. It was a continuous fever, although the patient said it was 'up and down' suggesting it was a spiking fever.
Moreover, where was the back pain? It was in her central back. Then, what type of pain? Was in continuous? Intermittent? Dull? Sharp? Associated with movement? Tearing? Worse on breathing deeply?
The importance of back pain can represent many different aetiologies here especially with fever such as a discitis, vertebral osteomyelitis, paravertebral abscess, myeloma, inflammatory arthropathies, metastatic disease, dissection, chest infection, pulmonary embolism, UTI, renal pain from rhabdomyloysis??....the list is extensive and by no means complete here, and by asking the right questions can lead the doctor to a more accurate idea of what is going on.
The patient had diarrhoea but it was not asked whether the diarrhoea was painful, the colour, the amount, whether there was any associated blood or mucus. This could possibly fit with inflammatory bowel disease which can cause diarrhoea (bloody), fever, fatigue, and arthropathy or a reactive arthritis / Reiter's Syndrome. The diarrhoea of course could be just due to antibiotic therpay!
Was the back pain due to pancreatic cancer invading the retroperitoneum and causing malabsortion and steatorrhoea?? The importance of asking the most minute details about diarrhoea cannot be taken lightly.
Were there night sweats? Weight loss? These questions needed to be asked and in addition, any history of TB exposure, chronic cough, haemoptysis-- TB can cause fever, and if it spread to the spine it may cause back pain too (Pott's disease).
The patient's past history included some congenital hip problems only and the patient had never smoked, did not drink alcohol and had never had a blood transfusion.
She was taking no medications apart from the antibiotic therapy.
No Family History or Detailed Social History was asked which is unfortunate as these may have given some clues.
Physical Examination: She was sleepy and hardly answered questions which may account for the paucity of history.
Temp: 39.1 Deg C, BP 82/40, SpO2 96% ? with Oxygen or Room Air. No Resp Rate or heart rate were recorded which in this situation was very important as the patient was clearly ill.
There were no meningeal signs-- no neck stiffness, No Kernig's Sign. Babinski was not performed.
The rest of the examination was described as normal.
Clearly, from the above examination, it was not entirely clear what the problem was with this patient.
However, the patient was clearly shocked and with a high fever and low blood pressure one has to consider Septic Shock as the primary problem.
Chest Xray revealed a left sided pneumonia. CT Chest again confirmed the pneumonia seen on chest xray.
WBC 11,200, Platlets 9.4 , CRP 29.3, INR 1.46, D-Dimer 2.7, [FDP not tested]
BUN 76, Creat 4.57, K 4.0, Na 128
Hb 10.3, MCV 84.2
AST 97, ALP 1434, gamma-GT 266, Bil 3.4 (Direct 2.4, Indirect 1.0), LDH 295, Alb 2.5
Urine: WBC 10-19. No bacteria. Myoglobin 1632.
ABG: pH 7.5, Low pCO2, HCO3 19.6, PO2 54.4 and BE -0.9
The above results signify severe problems for this patient including:
- Acute [probably Bacterial] Pneumonia with Hypoxaemia and Respiratory Alkalosis
- Disseminated Intravascular Coagulation
- Acute Renal Failure [probably from combination of Shock, Sepsis and Rhabdomyolysis]
- Severely abnormal liver function [? Shock Liver -- unlikely here as usually ALT and AST are very high in shock liver; this picture looks more obstructive]
No organism was identified by blood culture which may be due to previous antibiotic therapy.
She also received gamma-globulin, Anti-Thrombin III for the DIC and under went plasmaphoresis for endotoxin related shock and renal failure on several occasions.
The HDF was stopped when the plasma creatinine reached 0.94 although the bilirubin was now 5.7
Antibiotics were stopped 14 days after admission.
However, she was complaining of itching. She was otherwise saying that she felt well.
The most striking thing that was noticed was her tanned skin which was not the yellow one sees with Jaundice, but a tan from being in the Sun.
However, she said she never went out in the sun and she did not come from a Southern area of Japan. She said her skin had become increasingly tanned since last year BEFORE she was unwell with this acute problem. She otherwise was feeling well.
She had never had Hepatitis B or C infection and as mentioned, she did not drink alcohol.
This suggested, before examination, that the liver problem pre-dated the infection and was chronic in nature.
On examination, she looked well. There was no asterixis [liver flap], slight palmar erythema [red palms], and mild excoriations [scratch marks] on her arms.
She had deep tanning in exposed and non-exposed area of her skin.
JVP was not raised. No lymphadenopathy. Eyes were jaundiced. No liver breath [fetor hepaticus].
Pulse 80/minute, No heaves / Thrills. Heart sounds were normal. Mild peripheral pitting oedema.
Respiratory rate was 18/minute. Chest revealed some mild left basal crepitations [crackles] which did not clear on coughing consistent with resolving pneumonia.
Abdominaal Examination was abnormal: The patient had one spider naevus [vascular spider] on the left supraclavicular area. The liver was enlarged about 3 fingers below the costal margin and was mildly tender but smooth to the touch. Splenomegally could not be identified from palpation, but Traub's Space was Dull on percussion consistent with mild splenomegally.
Bowel sounds were normal.
The acute problem had clearly resolved.
However, she had obvious Hepatosplenomegally, Deeply Tanned Skin, Signs of Chronic Liver Disease and Liver Biochemistry consistent with an Obstructive Picture and particularly a High Alkaline Phosphatase.
The CT abdomen confirmed the physical findings and ultrasounds showed no dilatation of the Common Bile Duct.
Obviously, the above findings are consistent with Primary Biliary Cirrhosis. A differential diagnosis, if this were a Caucasian patient, would be Haemochromatosis especially because of the Deep Tanning of the skin.
Autoantibodies were performed and ANA was positive 160 (+), Anti-Mitochondrial M2 Antibody 49.4 (+)
Hence, the diagnosis here was likely to be PBC. It would fit the clinical features of this patient in that it is common in females aged between 30-60 years and approx 50% have no symptoms prior to diagnosis. Particular features include pruritis [itchy skin], tanning of the skin[due to increased Melanin deposition NOT BILIRUBIN], and smooth Hepatomegally in advanced stages. Most other causes of chronic liver disease produce a small liver. However, acute hepatitis can produce an enlarged liver.
PBC is associated with other autoimmune phenomena such as Sjogrens syndrome, autoimmune thyroiditis, CREST syndrome and autoimmune arthritides.
Most patients thesedays are identified by picking up blood abnormalities when asymptomatic with a raised ALP being one of the first signs.
Obviously, this patient had advanced disease and it is a surprise that it was not identified sooner than this when it could have been more amenable to therapeutic intervention.
Most patients are commenced on ursodeoxycholic acid as this is the only drug known to alter the natural history of PBC although it does not prevent chronic liver failure or the need for transplantation. Other drugs that have been used in the past include: colchicine and methotrexate although in randomisd trials they have shown no statistical benefit. [please see UpToDate 15.1 for further details]
It suggested that other causes of liver disease should also be ruled out including Haemochromatosis [ferritin level], Wilson's Disease [caeruloplasmin], and alpha-1-antitrypsin deficiency. Note that copper metabolism is abnormal in PBC and Keyser-Fleischer Rings can occur in these subjects.
An ERCP was recommended to rule out Primary Sclerosing Cholangitis.
Moreover, the patient would have needed a liver biopsy to confirm the diagnosis and stage of liver involvement.
Ultimately, the patient would require a liver transplant.
Other things to consider include checking levels of fat-soluble vitamins including A, D, K [ and E, but not clinically relevant]. Vitamin A deficiency can lead to night blindness in severe disease especially in those with raised bilirubin levels. A prolonged clotting time can be indicative of vitamin K deficiency and vitamin D deficiency can lead to osteomalacia. If levels are low, they need to be replaced.
Malabsorption can lead to steatorrhoea and reduced nutritional absorption. In such cases, either fatty acid intake is reduced and / or pancreatic enzyme substitutes are given.
The patient should have also been considered for a diagnostic-therapeutic upper GI endoscopy as the patient has a high risk for oesophageal varices even in the absence of obvious cirrhosis. Treatment consists of banding varices and reducing portal pressure with non-selective beta-blockers and calcium antagonists.
This case, once again, underlines the importance of obtaining a thorough history and physical examination.
Finally, causes of Hepatosplenomegally should be reviewed here and include:
- Liver disease and Elevated Portal Pressure including PBC
- Infections: Malaria, Schistosomiasis, Toxoplasmosis [cats: social history!], CMV, EBV, Acute Hep B, C infection, Weil's Disease [Rat's urine -- Social History!], Brucellosis [food history part of social history!]
- Haematological-Neoplasia: CML, CLL, Lymphoma, Extramedullary haematopoiesis of myeloporliferatice disease e.g. polycythema rubra vera
- Granulomatous: TB, Sarcoidosis
- Inflammatory: Amyloidosis
- Vascular: Budd-Chiari Syndrome
- Sun Related
- Dermatological: severe chronic eczema, freckles, acanthosis nigricans, chloasma [pregnancy related]
- SunTan Supplements e.g. Tanning Creams (がんがろ！！)
- Tattooing, arsenic exposure, gold, argyria.
- Drugs: chloroquine, chlorpromazine, minocycline, amiodarone.
- Topical Agents: benzoyl peroxide, tretinoin, flurouracil
- Berloque hyperpigmentation: phototoxicity from citrus or celery
- Drug Eruptions: Septrin, NSAIDs, Tetracyclines
- Oral Supplements: Beta-carotenaemia
- ACTH related: Primary Hypoadrenalism, ACTH secreting Pituitary adenoma, ACTH secreting tumours e.g. Ca Lung
- GI related: Haemochromatosis, Primary Biliary Cirrhosis, Wilson's Disease, Whipple's Disease, Hyperbilirubinaemia from any cause.
- Infection: Visceral Leishmaniasis