Tuesday, September 22, 2015

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Alcoholic liver disease

Chronic and excessive use of alcohol is one of the major causes of liver disease.

90% of daily heavy drinkers (>60 g alcohol/day) as well as binge drinkers have fatty liver but a smaller percentage (10-35%) of drinkers progress to alcoholic hepatitis which is a precursor for cirrhosis.

The long-term risk is 9 times higher in patients with alcoholic hepatitis compared to those with fatty liver alone.

Some population-based surveys have documented that men must drink 40 to 80 g of alcohol daily and women must drink 20 to 40 g daily for 10 to 12 years to achieve a significant risk of liver disease.

Liver pathology consists of 3 major lesions that are progressive and rarely exist in a pure form:
1) fatty liver (usually reverses quickly with abstinence),
2) alcoholic hepatitis and
3) cirrhosis.

histologic staging alcoholic liver disease

Prognosis of severe alcoholic liver disease (ALD) is bad. Mortality of patients with alcoholic hepatitis concurrent with cirrhosis id nearly 60% at 4 years.

Although alcohol is a direct hepatotoxin, it is unclear why only 10-20% of alcoholics will develop alcoholic hepatitis. It appears to involve a complex interaction of facilitating factors like drinking patterns, diet, obesity and gender.

Harmful use of alcohol results in 2.5 million deaths each yr. Most of the mortality is due to cirrhosis. The mortality is declining now because of decreased consumption of alcohol in the Western countries except in the U.K, Romania, Russia and Hungary.

a) Quantity and duration of alcohol intake - are the most important risk factors. Time taken to develop liver disease is directly related to the amount of alcohol consumed.
b) There is no clear role of the type of beverage and the pattern of drinking.
c) Genetic - some people are genetically predisposed  for alcoholism and subsequently to the ill effects of alcohol on the liver.
d) Gender - It is a strong determinant for ALD. Women are more susceptible to alcoholic liver injury. They develop advanced liver disease with substantially less alcohol intake. Gender-dependent differences may be due to the effects of estrogen, proportion of body fat and gastric metabolism of alcohol.
e) Chronic infection with Hepatitis C virus - It is an important comorbidity in the progression of ALD to cirrhosis in chronic and excessive drinkers. Even moderate alcohol intake of 20-50 g/day increases the risk of cirrhosis and hepatocellular cancer. Intake of more than 50 g/day decreases the efficacy of interferon-based antiviral therapy.

It is unclear but what is known is that alcohol can act as a direct hepatotxin and malnutrition does not play a major role.
- Alcohol is metabolised to acetyldehyde which in turn initiates an inflammatory cascade that results in a variety of metabolic responses.
- Steatosis from lipogenesis, fatty acid synthesis and depression of fatty acid oxidation occur secondary to effects on sterol regulatory transcription factor (SRTF) and peroxisome proliferator-activated receptor alpha (PPAR-alpha).
- Intestinal derived endotoxin initiates a pathogenic process through toll-like receptor-4 and TNF-alpha. This facilitates hepatocyte apoptosis and necrosis.
- Cell-injury endotoxin also activates innate and adaptive immunity pathways. There is release of pro-inflammatory cytokines (TNF-alpha) and proliferation of T/B cells.
- Production of toxic protein-aldehyde adducts, generation of reducing equivalents and oxidative stress also contribute to liver injury.

Finally hepatocyte injury and impaired regeneration are associated with stellate cell activation and collagen production which are key events in fibrogenesis. The resulting fibrosis causes architectural derangement of the liver and the associated pathophysiology.

Fatty liver is the initial and most common histologic response to hepatotoxic stimuli, including excess alcohol ingestion. Accumulation of fat within the perivenular hepatocytes coincides with the location of alcohol dehydrogenase. Continuing alcohol ingestion results in deposition of fat throughout the entire hepatic lobule.

Alcoholic fatty liver - traditionally regarded as benign but appearance of steatohepatitis and certain features like giant mitochondria, perivenular fibrosis and microvesicular fat are associated with progressive liver injury.

Hallmarks of alcoholic hepatitis include: (hepatocyte injury)
a) ballooning degeneration,
b) spotty necrosis,
c) polymorphonuclear infiltrate and
d) fibrosis in the perivenular and perisinusoidal space of Disse.

Mallory-Denk bodies are often present in florid cases but these are neither specific nor necessary to establish the diagnosis.

Usually the patients are asymptomatic.
Hepatomegaly is often the only clinical finding.
It is very important to assess the drinking history and estimate how much alcohol is consumed per day and for how long.
1 beer, 4-5 ounces of wine, 1.5 oz of 40% liquor and 1 ounce (approximately 30 mL) of 80% spirits all have around 12 g of alcohol.

Alcohol content of various beverages

- Patients with fatty liver may have:
1) right upper quadrant discomfort,
2) nausea and
3) rarely jaundice.

- Patients with alcoholic hepatitis may have:
1) fever
2) spider nevi
3) jaundice
4) abdominal pain.
We can also see portal hypertension, ascites and variceal bleeding even in the absence of cirrhosis.

These are most identified through routine screening tests.

Fatty liver - laboratory abnormalities are non-specific
Modest elevation of AST, ALT, GGTP are seen. Triglycerides and bilirubin may also be increased.

Alcoholic hepatitis
a) increased AST and ALT - by 2-7 fold but rarely greater than 400 IU.
b) AST/ALT ratio greater than 1.
c) hyperbilirubinemia
d) modest increase in alkaline phosphatase

If synthetic function is deranged then the condition is more serious. Hypoalbuminemia and coagulopathy are more common in advanced liver disease.

Ultrasonography is also a useful investigation as it can determine the size of the liver and detect any fatty infiltration. If it demonstrates portal vein flow reversal, ascites and intraabdominal venous collaterals then the condition has less potential for complete reversal.

Below is an ultrasonographic picture of hepatic steatosis. Fatty infiltration produces an increased reflectivity of hepatic parenchyma, known as ‘bright liver pattern’. This feature can be assessed by comparing liver parenchyma with the right kidney’s cortex, which normally presents an echogenicity equal to or slightly lower than that of the liver. Severe steatosis produces a strong attenuation in the deepest liver sections, resulting in poor explorability.

bright liver with posterior attenuation

Critically ill patients with alcoholic hepatatis have short term (30-day) mortality rates exceeding 50%.
A Discriminant Function (DF) above 32 and a Model for End-stage Liver Disease (MELD) greater than 21 is associated with poor prognosis.
Worse prognosis if there is associated:
a) ascites,
b) variceal hemorrhage,
c) deep encephalopathy and
d) hepatorenal syndrome.

mortality alcoholic liver disease

a) Complete abstinence from alcohol is the mainstay for treatment.
b) Patients with severe alcoholic hepatitis i.e. DF>32 and MELD>21 should be given Prednisone 40mg/day or Prednisolone 32mg/day for 4 weeks followed by tapering over 4 weeks.
c) Alternatively Pentoxifylline, a non-specific TNF inhibitor, can be used in a dosage of 400mg 3 times per day for 4 weeks.
d) Liver transplantation is an accepted indication for treatment in selected and motivated patients with end-stage cirrhosis.

Below is an algorithm showing how to manage alcoholic hepatitis:
algorithm alcoholic hepatitis

N.B Monoclonal antibodies that neutralize serum TNF-alpha should not be used as studies have reported an increase in the number of deaths secondary to infections and renal failure.

First published on: 23 September 2015

Wednesday, September 2, 2015

Voltaire - Medical quote no longer valid

Times have changed Monsieur Voltaire.

Your quote is no longer valid in our "Evidence Based Medicine" world.

The quote's accuracy is stunning though if applied to quacks.

Our advice to young practitioners : DO NOT BLINDLY FOLLOW WHAT A SENIOR DOCTOR IS DOING.
Try to  understand why he did something for that specific problem.

Always ask if you do not understand.

Article resources:
1) "Voltaire lisant L’année littéraire de Fréron", huile sur toile de Jacques Augustin Catherine Pajou, 1811

Last reviewed on: 2 September 2015

Sunday, July 19, 2015

Menopause - Definition, symptoms and hormone replacement therapy

 Menopause  refers to a point in time that follows 1 year after the permanent cessation of menstrual periods that occurs naturally or is induced by surgery, chemotherapy or radiation.

On average, natural menopause occurs between 50 and 51 years (range 45–59) and is part of the process of normal ageing. It has been noted that smoking advances the age of menopause by approximately 2 years.
The diagnosis can only be made retrospectively and it is usually preceded by months or years of irregular cycles, that is not associated with some other physiological or pathological causes.

If the cessation of menses occurs before the age of 40, then it is referred to as the "Premature ovarian failure".
The older terms perimenopause or climacteric generally refer to the time period in the late reproductive years, usually late 40s to early 50s. Characteristically, it begins with menstrual cycle irregularity and extends to 1 year after permanent cessation of menses. The more correct terminology for this time is menopausal transition. This transition typically develops over a span of 4 to 7 years, and the average age at its onset is 47 years

Up to 75% of women will experience adverse symptoms related to menopausal transition while the others may not have any symptoms at all. Although symptoms associated with menopause occur as a result of oestrogen deficiency, replacing it is not always the treatment of choice.
The use of HT should be made on an individual basis, after careful consideration of quality of life and personal risk factors. In addition to any pharmacological treatments considered, lifestyle modifications are essential.

Below a few of the symptoms are discussed and whether hormone replacement may be helpful:

Hot flushes are characterised by a feeling of intense warmth, often accompanied by profuse sweating, anxiety, skin reddening and palpitations. They are sometimes followed by chills.
In most cases, they will resolve in around 1 year or less without any treatment.
1/3 rd of the patients will have symptoms for up to 5 years after natural menopause and in 20% they may persist for up to 15 years or more.
Menopause induced by surgery is associated with about a 90% probability of hot flushes during the first year. In these cases, symptoms are often more abrupt and severe and can last longer than those associated with a non-surgical menopause.

Hormone therapy is the most effective (80% efficacy) treatment for vasomotor symptoms associated with menopause at any age, but benefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopause.
Extra care must be taken in women with a history of hormone-dependent cancer, e.g. breast cancer.

Genitourinary symptoms due to menopause can affect up to 50% of women, however it is under diagnosed and under treated. The pathology here is that there is a loss of estrogen which results in urogenital ageing. The tissues of the vaginal walls becomes thinner since the amount of collagen and elastin is reduced. The walls become pale, thin and lose their elasticity. A reduction in vaginal secretions and decreased tissue elasticity also increases the susceptibility to trauma and pain or irritation during or after intercourse.

In addition to vulvo-vaginal symptoms, the less acid pH of the estrogen-deficient vagina increases the likelihood of urinary tract infections.

Vaginal symptoms become apparent 4–5 years after the menopause. 25–50% of all postmenopausal women have some objective changes as well as subjective complaints.
Symptoms may include vaginal dryness (75%), dyspareunia (38%), vaginal itching, burning and pain (15%).
Locally administered vaginal estrogens (creams, pessaries, tablets and vaginal rings) are equally effective in the treatment of menopause-related vulval and vaginal symptoms. Local estrogen therapy will lower vaginal pH, thicken the epithelium, increase blood flow and improve vaginal lubrication.

There are no evidence to support the use of hormone replacement for the urinary symptoms.

The decline in estrogen results in a decrease in the bone mineral density and a subsequent significant increase in the prevalence of osteoporosis.

General management includes:
1) assessment of the risk of falls and their prevention,
2) maintenance of mobility and
3) correction of nutritional deficiencies, particularly of calcium, vitamin D and protein.

Pharmacological interventions include bisphosphonates, denosumab, parathyroid hormone peptides, raloxifene and strontium ranelate. All have been shown to reduce the risk of vertebral fracture and some have been shown to reduce the risk of non-vertebral fractures. However, all are associated
with side effects and many women will fail to comply.
Hormone therapy reduces the risk of spine and hip, as well as other osteoporotic fractures even in women at low risk. It would appear that half of the traditional bone conserving doses are effective in conserving bone mass and are successful means of fracture prevention. However, hormone replacement is not the first line therapy in treating post menopausal osteoporosis.

The incidence of CVD increases with age and menopause may have an adverse effect. Hormone therapy was thought to confer CVD risk reduction but some studies demonstrated an increased number of coronary heart disease events and strokes and concluded that the risks outweighed the benefits. These studies were carried out on elderly women though and probably there was already an element of atherosclerosis that influenced the outcomes. Recent studies suggest that if hormone replacement is started soon after menopause, it may actually be beneficial.

Since the sex hormones are known to be thrombogenic there is an expected increase in the risk of deep vein thrombosis and stroke when using oral replacement therapy. The risk is further increase if the patient is a smoker.

Tuesday, April 21, 2015



Homocysteine is a sulphur containing amino acid that is produced during the conversion of methionine to cysteine.

Hyperhomocysteinemia results when there is an abnormality in the homocysteine metabolism.
It is an independent risk factor for stroke, MI, peripheral arterial disease and venous thrombotic disease.

Even mild to moderate hyperhomocysteinemia is a significant risk factor for vascular disease.


The amino acid homocysteine is normally metabolized via the transsulfuration pathway by the enzyme cystathionine-β-synthase (CBS), which requires vitamin B6 as co-factor and via the
remethylation pathway by the enzymes methylenetetrahydrofolate reductase (MTHFR),
which is folate dependent and methionine synthase, which requires vitamin B12 as co-factor.

1 - Methylenetetrahydrofolate reductase
2 - Methionine synthase

Hyperhomocysteinemia can be either:
1) Inherited or
2) Acquired.

Inherited severe hyperhomocysteinemia (plasma level >100 µmol/L), as seen in classic homocystinuria, may result from homozygous MTHFR and CBS deficiencies and more rarely from inherited errors of cobalamin metabolism. Classic symptoms for homozygous patients include premature vascular disease and thrombosis, mental retardation, ectopic lens and skeletal abnormalities.

Inherited mild to moderate hyperhomocysteinemia (plasma level >15 to 100 µmol/L) may result from heterozygous MTHFR and CBS deficiencies, but most commonly results from the thermolabile variant of MTHFR (tlMTHFR) that is encoded by the C677T gene polymorphism. Heterozygous carriers of the tlMTHFR mutation have normal plasma homocysteine levels unless folate levels are

Acquired hyperhomocysteinemia may be caused by folate deficiency, vitamin B 6 or B 12 deficiency, renal insufficiency, hypothyroidism, type II diabetes mellitus, pernicious anemia, inflammatory bowel disease, advanced age, climacteric state, carcinoma (particularly involving breast, ovaries or pancreas) and acute lymphoblastic leukemia, as well as methotrexate, theophylline and phenytoin therapy.

VTE risk is most closely related to elevated fasting plasma homocysteine levels, regardless of etiology. Hyperhomocysteinemia (plasma level >18.5 µmol/L) has been associated with a two- to fourfold increased VTE risk.

The precise mechanisms underlying the thrombogenicity of homocysteine remain unclear. Several diverse mechanisms have been proposed, including endothelial cell desquamation, low-density lipoprotein (LDL) oxidation, promotion of monocyte adhesion to endothelium and factor V activation and promotion of thrombin generation.
Homocysteine also enhances platelet aggregation and adhesiveness as well as turnover, presumably as a result of endothelial cell injury.

Laboratory Diagnosis:
The initial step in the evaluation of the patient with suspected hyperhomocysteinemia involves measurement of fasting total plasma homocysteine (the sum of nonprotein-bound and proteinbound).
A normal value in the nonfasting setting does not normally require repeating.

Standardized methionine loading test
Testing 2 to 8 hours after an oral methionine load (100 mg/kg) increases the sensitivity of detecting occult vitamin B6 deficiency and obligate heterozygotes for CBS deficiency, but methionine loading is not routinely recommended.
Vitamin B12 and folate deficiency do not affect post-methionine loading homocysteine values.
After 4-6 hours the level of homocysteine is measured again.
A level 5 times that of the fasting one or an increase by 40 µmol/L is considered a positive test for hyperhomocysteinemia.
In patients found to have elevated levels of homocysteine, testing for vitamin B12 deficiency is advocated to avoid missing subclinical deficiency before
beginning oral folic acid therapy.

1) Folic acid supplementation is the mainstay therapy. The usual recommended dose is 0.4 to 1.0 mg daily. This causes a 25% decrease in the homocysteine level.
2) Because patients with subclinical vitamin B12 deficiency may be prone to developing
peripheral neuropathy if they receive folic acid supplementation alone, additional treatment with 0.5 mg/day of oral vitamin B12 has been advocated. An additional 7% reduction of homocysteine levels was noted with vitamin B12 supplementation.
Vitamin B12 administration results in normalization of homocysteine levels in B12-deficient individuals. In these patients, a monthly intramuscular injection of 200 to 1,000 µg of vitamin B12 is considered adequate replacement.
3) Vitamin B6 supplementation did not appear to have any effect on homocysteine levels.
4) Thrombotic events in hyperhomocysteinemic patients should be treated accordingly.

Monday, March 9, 2015

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kussmaul breathing pattern - description and causes

This type of breathing pattern was first described by Adolph Kussmaul, a german physician in 1874. He noticed that his patients with diabetic ketoacidosis had a pattern of breathing which he first labelled as having "air hunger".

In the Kussmaul type of breathing, the patient is breathing heavily i.e hyperventilating along with tachypnea.
So we will find that the amplitude of the breaths along with the rate will be increased.
There is usually no pauses between the breaths.

This is not specific for diabetic ketoacidosis. It can also appear in other types of severe metabolic acidoses e.g alcoholic ketoacidosis .

Sunday, February 15, 2015

Adverse effects of Amiodarone

1) Hypotension can occur especially with the intravenous form due to vasodilation and depressed myocardial performance. Long-term oral therapy can also cause depressed contractility but it is unusual.

2) Nausea can sometimes be seen during the loading phase. All we have to do is to decrease the daily dose of the medication.

3) Pulmonary fibrosis is the most serious adverse effect during chronic amiodarone therapy. The fibrosis can be rapidly progressive and fatal. The risk factors include: underlying lung disease, doses of 400 mg/day or more and recent pulmonary insults such as pneumonia. Early amiodarone toxicity can be detected using pulmonary function tests and serial chest X-rays.

4) Other adverse effects that may be seen during long-term therapy include
a) corneal microdeposits (which often are asymptomatic),
b) hepatic dysfunction,
c) vivid and disturbing dreams
d) neuromuscular symptoms (most commonly peripheral neuropathy or proximal muscle weakness), e) photosensitivity and
f) hypo- or hyperthyroidism.

Sunday, February 8, 2015


Aminoglycosides - why -mycin and -micin

The aminoglycoside group includes gentamicin, amikacin, netilmicin, kanamycin, tobramycin, streptomycin, paromomycin and neomycin.

These drugs have a good action against aerobic gram-negative bacteria.

They are rapidly bactericidal. Bacterial killing is concentration dependent: The higher the concentration, the greater is the rate at which bacteria are killed.

As noted above, some of the names end by -micin while others by -mycin. The reason behind this lies in the origin of the antibiotics.

All the antibiotics ending with -mycin are either natural products or semisynthetic derivatives of compounds produced by a variety of soil actinomycetes notably Streptomyces.
Those ending with -micin are derived from other actinomycetes e.g Micromonospora.

Saturday, January 24, 2015

Atrial septal defect device closure

This procedure is called as Atrial septal defect (ASD) device closure.

Transesophageal echocardiography (TEE) is must before procedure for:
1) actual sizing of the defect
2) defining the rims - to hold device in place
3) ruling out anomalous pulmonary venous drainage
4) ruling out significant mitral regurgitation (MR).
Intraprocedural TEE is not mandatory.

N.B How to distinguish between an ASD device and a patent foramen ovale (PFO) device? Left atrial (LA) disk (green arrow) is larger than Right atrial (RA) disk (yellow arrow), thus it is an ASD device.For a PFO device, RA disk will be larger than LA disk.

Further readings: