Pentoxifylline in Severe Alcoholic Hepatitis: A Prospective, Randomised Trial

Sandeep Singh Sidhu, Omesh Goyal, Monika Singla, KL Bhatia, Rajoo Singh Chhina, Ajit Sood

INTRODUCTION
Severe Alcoholic hepatitis (SAH), defined by modified Maddreys Discriminant Function (DF) 32, is associated with significant morbidity and mortality.

Of the various treatment modalities evaluated for treatment of SAH, corticosteroids have been the most extensively studied. Five out of 13 RCTs, and four out of 5 meta-analysis have shown a survival benefit with corticosteroids, especially in patients with DF 32 and/or encephalopathy.

 However, the role of corticosteroids in SAH still remains somewhat controversial. Corticosteroid therapy is not considered the ideal option by all authors because their beneficial effect seems to be confined to a highly selected minority group in which the inhibitory effect of corticosteroids on liver inflammation is NOT outweighed by side effects such as weakened defence against infections, anti-anabolic effects, and possible ulcer promoting effects. Also corticosteroids are contraindicated in patients with renal failure, gastro-intestinal (GI) bleed, pancreatitis and active sepsis.

 Pentoxifylline (PTX), a non-selective phosphodiesterase inhibitor, also decreases the production of TNF-, IL-5, IL-10 and IL-12.
A prospective, randomised trial showed significantly lower mortality in SAH patients who received PTX compared to controls (24.5% versus 46.1%). The survival benefit of PTX seemed to result from a decrease in risk of hepato-renal syndrome, unlike corticosteroids which seem to lead to an improvement in hepatic function. Unlike corticosteroids, clinical trials to assess the efficacy of PTX in SAH are scarce.

METHODOLOGY
Prospective, Randomised Trial conducted in a tertiary care institute of northern India.
INCLUSION CRITERIA : 1) Patients with clinical features suggestive of alcoholic hepatitis i.e. History of chronic alcoholism, recent onset of jaundice, fever, tender hepatomegaly 2) Patients with DF > 32 EXCLUSION CRITERIA : 1) Positive viral serology 2) Concomitant infections 3) Active GI haemorrhage 4) Severe cardiovascular or pulmonary diseases 5) A decline in DF < 32 with symptomatic treatment for 5-7 days

 Routine investigations including biochemical liver tests, prothrombin time index and markers for hepatitis A, B, C and E viruses were done. Patients were randomised into 2 groups using sequentially numbered (table of random numbers), sealed, opaque envelopes. PTX group received tablet PTX 400 mg thrice daily for 28 days. Control group received placebo (vitamin tablets) for 28 days. Patients were recommended a diet constituting 2500-3000 calories, and 1 g/kg proteins. All investigations were repeated twice weekly or earlier if required. Serum TNF levels were done at initiation and end of therapy.

 Statistical analysis was done using Fischers exact test for qualitative variables, and Mann Whitney test for quantitative
variables. Multiple logistic regression analysis was used for differences between survivors and non-survivors. P-value of <0.05 was considered significant. Primary outcome measure was effect of PTX on short term (28 day) mortality. Secondary outcome measures were- effect of PTX on improvement in DF (defined as 50% reduction in DF from randomisation to end of therapy), and improvement in renal dysfunction (defined as reduction in serum creatinine to < 1.5 mg/dl from a higher value).

RESULTS
MOTRALITY & MORBIDITY : At 4 weeks, mortality in PTX group was 20% (5/25), and that in controls was 40% (10/25) (p=0.216; RR 0.5; 95% CI 0.19-1.25). All deaths occurred due to progressive hepatic failure, either alone or in combination with other terminal events. In PTX group, GI bleed was pre-terminal event in two patients, septicemia in two, and renal failure in one patient. Among controls, GI bleed was pre-terminal event in three, and renal failure in seven patients. Renal failure was the cause of mortality in 20% (1/5) patients in PTX group, and 70% (7/10) patients in controls (p=0.11).

CHANGE IN RENAL FUNCTIONS :

At 4 weeks, there was a significant reduction in urea and creatinine in PTX group but not in controls. At the end of therapy, PTX group showed a significant reduction in the number of patients having renal dysfunction as compared to controls.
CHANGE IN HEPATIC FUNCTIONS : A significant decrease in DF was noted in PTX group at end of therapy (p=0.00) while controls showed an increase in DF. Also, number of patients showing improvement in DF by >50% of baseline was significantly more in PTX group {66.7% (12/18) versus 7.1% (1/14), (p= 0.0009)}

TNF & OTHER LAB PARAMETERS : PTX group showed a significant decrease in TNF, bilirubin, PTI and AST levels; and a significant increase in serum albumin.

THUS ..
The present study confirmed the beneficial effect of PTX on renal functions and on reduction in short-term mortality in SAH. In addition, significant improvement in hepatic functions in PTX group was an important finding.

CONCLUSION
PTX leads to a significant improvement in hepatic and renal functions in patients with SAH. PTX leads to a trend towards decreased mortality. Thus, PTX is a useful treatment option for patients with SAH.

END OF ORIGINAL ARTICLE

Advances in Small Bowel Imaging Capsule Endoscopy

- Praveen Sharma

INTRODUCTION
The small bowel has been a difficult area to examine due to its anatomy, location and relative tortuosity. Capsule endoscopy technology has revolutionized the imaging of small bowel. Capsule endoscopy (CE) was launched at the beginning of this millennium. Small bowel CE, therefore, represents a major advance as it is a safe, non-invasive procedure and it is cost-effective in a variety of clinical situations. This technique evaluates endoscopically, with high resolution images, the whole small bowel, avoiding any sedation, surgery or radiation exposure. Currently, CE is recommended, after a negative gastroscopy and colonoscopy in patients with obscure gastrointestinal bleeding.

 CE is also useful in other clinical situations, such as detection of small bowel lesions in Crohns disease, non steroidal antiinflammatory drug enteropathies, celiac disease, small bowel polyposis syndromes and small bowel tumours.

What is Capsule Endoscopy?

CE is performed by ingestion of a small (2611 mm) disposable battery powered pill containing a complementary metal oxide semiconductor camera which provides a field of view of 156, a variable depth of view (1-30 mm), and a resolution of 0.1 mm. Four light emitting diodes illuminate the lumen of the bowel. PROCEDURE : Patient need to remain following 8-10 hours fasting when the capsule is swallowed. Eight skin leads are placed to the patients anterior abdominal wall and connected to the hard drive. The camera is activated by removal of the capsule from its magnetic holder.

 Camera takes 2-3 images per second and transmits these by means of radio frequency to a sensor array placed on the patients abdomen and from here to a recording device in a belt that the patient wears for the duration of the battery life (8-10 h). Now the patient swallows the capsule with a few sips of water, then the capsule is passively moved along by peristalsis. Two hours after ingestion, the patient is allowed to drink, while eating is allowed after 4 h. After the 10-12 hours recording device is removed and the recorded images are downloaded to the computer. It takes an average 40-60 min to read these images. Since its development, additional support systems have been added to the software to assist the reader, such as localization capability, suspected blood indicator, a multiviewing feature and quick view modality. The capsule is excreted with the feces, usually within 24 to 48hrs.

Indications for Capsule Endoscopy

Obscure gastrointestinal bleeding

Small bowel Crohns disease

Assessment of coeliac disease Screening and surveillance for polyps in familial polyposis syndromes

Contraindication for Capsule Endoscopy

Patients with known or suspected GI obstruction, strictures, or fistulas based on the clinical picture or pre-procedure testing Patients with cardiac pacemakers or other implanted electromedical devices Patients with swallowing disorders Pregnancy

ADVANTAGES
CE now has an established role in patients with persistent obscure gastrointestinal bleeding (OGB) who have had a negative gastroscopy and colonoscopy. The diagnostic yield of capsule endoscopy, with other procedures, in patients with OGB confirmed the superiority of CE over other procedures for imaging the small bowel.

DISADVANTAGES
The retention of the device is the main complication of the procedure and is defined when CE remains in the digestive tract for a minimum of 2 wk. A plain abdominal radiograph should be obtained to confirm excretion of capsule if the video fails to show that it enters the colon. Patient should not undergo magnetic resonance imaging after CE until the capsule as passed out.

Esophageal Capsule Endoscopy

The oesophageal capsule measures 1126 mm and acquires video images from both ends of the device (14 frames/s). Moderately high sensitivity and accuracy in the diagnosis and surveillance of Barrett esophagus in patients with gastroesophageal reflux disease. In patients with portal hypertension, ECE has a sensitivity of 63% to 100% for screening of esophageal varices.

Colon Capsule Endoscopy

Useful in the diagnosis of colorectal cancer when colonoscopy is incomplete or contraindicated. The reported sensitivity varied from 50% to 70%, and specificity from 73% to 100% , when comparing colon capsule with colonoscopy for the detection of polyps. CCE has also been shown to detect a variety of lesions such as diverticulosis, proctitis, angiomas and melanosis coli.

Conclusion
Capsule endoscopy is a reliable, well accepted and tolerated by the patients, which allows complete exploration of the small intestine. CE offers the advantages of total bowel visualization during a single examination, and helps the endoscopist in deciding the rout for doing deep enteroscopy.

END OF REVIEW ARTICLE

CASE REPORT
A k/c/o PSORIASIS PRESENTING WITH ABDOMINAL DISTENSION & LEG SWELLING

HISTORY
A 67 yr old male with c/c abdominal distension since 3 months c/o B/L leg swelling c/o loss of apetite

NEGATIVE HISTORY : No h/o decrease in urine output No h/o chest pain / palpitations No h/o jaundice No h/o TB / tuberculosis contacts No h/o haematemesis / malena No h/o abdominal distension in past No h/o smoking / alcohol use No h/o DM / HT

Past history
k/c/o Psoriasis for last 35 years, on weekly methotrexate therapy (7.5 mg) since last 15 yrs On topical therapy initially, but later shifted to methotrexate by treating physician Psoriatic lesions within control with weekly mtx therapy Liver function monitored periodically which were essentially normal except once when SGPT was raised less than twice the upper limit of normal Not taking NSAIDs, PUVA therapy or any other hepatotoxic drug

EXAMINATION
Alert, stable vitals Mild pallor Spider angiomata over upper trunk Pitting pedal edema Psoriatic plaques over the extensor surface of legs & forearms & over the back of chest Abdominal distension with shifting dullness Liver span 9 cm , moderately enlarged spleen Rest of general & systemic examinations were essentially normal

INVESTIGATIONS
Hb = 9.5 gm/dl TLC = 8300 / cu. mm Platelets = 1.2 lakh/ cu. mm PCV = 29 % MCV = 84 % SGOT = 44 IU/L SGPT = 33 IU/L ALP = 114 IU/L Bilirubin : T = 1.3 mg/dl, D = 0.7 mg/dl INR = 1.44 SAAG = 2.2

 USG Abdomen - normal sized liver with coarse parenchymal echo texture and nodular surface outline. Portal vein diameter was 13 mm at porta. Spleen was enlarged with a span of 14.8 cms, splenic vein diameter was 8 mm at porta. Moderate amount of free fluid was seen in pelvis and paracolic gutters. UPPER GI ENDOSCOPY - 2 oesophageal varices of grade III.

DIAGNOSIS : k/c/o Psoriasis /w cirrhosis of liver /w portal hypertension /w ascitis /w oesophageal varices

DISCUSSION
There have often been doubts to the possibility of psoriasis per se being the cause of cirrhosis, but unfortunately, not enough or recent studies are there to clear the air on this. This patient was on weekly oral methotrexate therapy, taking 7.5 mg tablet every week for the past 15 years, amounting to total cumulative dose of 5.85 g till the presentation of symptoms related to cirrhosis. The long duration of therapy is the risk factor in this patient. The duration of methotrexate therapy, age, daily oral methotrexate dosage schedule, risk factors for non-alcoholic steatohepatitis (obesity, diabetes mellitus, and glucose intolerance) and concurrent alcohol ingestion have been identified as significant risk factors in the evolution of hepatic fibrosis in patients taking methotrexate.

 Concurrent PUVA therapy has also been suggested to cause derangements in liver function, but this patient was not on topical therapy for psoriasis for last more than 15 years. Many studies have found that abnormal liver function tests are often encountered during the treatment of psoriasis with methotrexate. But studies as early as in 70s have found that clinical signs of serious hepatic damage may be the first indication of cirrhosis and that liver function studies might not be reliable indicators of pathologic changes found on liver biopsy. This underlines the need of proper selection of patients and monitoring of therapy based on periodic liver biopsy, without banking solely on liver function tests.

 Not all cases of methotrexate-induced hepatotoxicity may be detected by liver function tests, and liver biopsy is still considered the most reliable method of detecting hepatotoxicity in patients treated with methotrexate.

The American Academy of Dermatology recommends that sequential liver biopsies should be performed at a cumulative dose of 1-1.5 g and repeated at cumulative dose intervals of 15 g thereafter.
The presence of pathological changes detected by the liver biopsy should direct the decision of whether or not to continue methotrexate therapy.

 Patients with grade I or II histological changes (without fibrosis) can continue methotrexate; patients with grade IIIA changes (mild fibrosis) can continue methotrexate with a repeat liver biopsy after 6 months; patients with grade IIIB changes (moderate to severe fibrosis) or grade IV changes (cirrhosis) should discontinue methotrexate.

There is a need to guard against the false sense of security rendered by normal results of liver function tests and to perform serial liver biopsies starting at cumulative dose of 1.5g in patients on methotrexate therapy.

TREATMENT
Haematinics, Diuretics Band ligation for oesophageal varices Tapering off of methotrexate & topical therapy for psoriasis

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