Terry Gramlich

Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity

BACKGROUND & AIMS The spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up and have not carefully delineated different histological types when determining clinical outcomes. The aim of this study was to compare clinical characteristics and outcomes of patients with different types of nonalcoholic fatty liver. METHODS All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related mortality. RESULTS Of 772 liver biopsy specimens, complete data were available in 132 patients. Fatty liver (type 1) did not differ from the other three types combined with respect to gender, race, age, or obesity. Cirrhosis was more common in the other types combined (22%) than fatty liver alone (4%; P </= 0.001). Overall mortality, histological iron, and hepatitis C did not differ between groups. Most of the liver-related deaths were in type 4. CONCLUSIONS The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver. These poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.

Long-Term Follow-Up of Patients With Nonalcoholic Fatty Liver

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) convincingly. NASH is the only subtype of NAFLD that has been shown to progress relatively, although these findings were reported from studies with short follow-up periods. We assessed the long-term outcomes of a NAFLD cohort. METHODS Patients with NAFLD established by biopsy were identified in databases and categorized as NASH or non-NASH. Mortality data and causes of death were obtained from National Death Index Plus. The nonparametric Kaplan-Meier method with log-rank test and multivariate analyses with a Cox proportional hazard model were used to compare different NAFLD subtypes and to identify independent predictors of overall and liver-related mortality. RESULTS Of 173 NAFLD patients (age at biopsy, 50.2 +/- 14.5 y; 39.9% male; 80.8% Caucasian; 28.9% with type II diabetes), 72 (41.6%) had NASH and 101 (58.4%) had non-NASH NAFLD. Over the follow-up period, the most common causes of death were coronary artery disease, malignancy, and liver-related death. Although overall mortality did not differ between the NAFLD subtypes, liver-related mortality was higher in patients with NASH (P < .05). Independent predictors of liver-related mortality included histologic NASH, type II diabetes, older age at biopsy, lower albumin levels, and increased levels of alkaline phosphatase (P < .05). CONCLUSIONS This long-term follow-up evaluation of NAFLD patients confirms that NASH patients have increased liver-related mortality compared with non-NASH patients. In addition, patients with NAFLD and type II diabetes are especially at risk for liver-related mortality.

The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression

OBJECTIVE:The reported risk of progression from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or carcinoma (CA) in Barretts esophagus varies. However, the validity of a diagnosis of LGD may be questioned because of interobserver variability.METHODS:A search of the Cleveland Clinic Foundation surgical pathology files between 1986 and 1997 yielded biopsy specimens from 43 patients with Barretts esophagus diagnosed and coded as LGD. Patients with concurrent or prior diagnoses of HGD or carcinoma were excluded. The LGD cases were randomized and blindly reviewed by three gastrointestinal (GI) pathologists along with cases originally diagnosed as Barretts esophagus without dysplasia (ND; n = 28), indefinite for dysplasia (IND; n = 14), or HGD (n = 15). Each pathologist classified every biopsy specimen as ND, IND, LGD, or HGD, and interobserver agreements were determined by kappa statistics (K). Follow-up data were available on 25 patients originally diagnosed with LGD. Progression was defined as a subsequent diagnosis of HGD or CA on esophageal biopsy or resection specimens.RESULTS:Agreement between two GI pathologists for a diagnosis of LGD was fair (K = 0.28) and poor (K = 0.21 and −0.04). Individual GI pathologists agreed with the original diagnosis of LGD in 70%, 56%, and 16% of cases. The 25 patients with follow-up included 21 men and four women (mean age, 67 yr) with a mean follow-up of 26 months (range: 2–84 months). Seven patients (28%) with follow-up developed HGD (five patients) or CA (two patients), 2–43 months (median: 11 months) after a diagnosis of LGD. The individual GI pathologists’ diagnosis did not correlate with progression. However, when at least two GI pathologists agreed on LGD, there was a significant association with progression (seven of 17 patients, 41%, p= 0.04). When all three GI pathologists agreed on a diagnosis of LGD, four of five patients progressed (p= 0.012). In contrast, of the eight patients with follow-up and no agreement among GI pathologists for a diagnosis of LGD, none progressed.CONCLUSIONS:A high degree of interobserver variability is seen in the histological diagnosis of Barretts esophagus–related LGD. Although the number of observations is low, a consensus diagnosis of LGD among GI pathologists suggests an increased risk of progression from LGD to HGD or carcinoma.

Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is reported commonly in patients with type 2 diabetes mellitus (DM), which has been suggested as a risk factor for the progressive form of NAFLD, or nonalcoholic steatohepatitis. The aim of this study was to assess the outcome of patients with NAFLD and DM. METHODS A cohort of patients with NAFLD was identified, and patients with other causes of liver disease (alcohol, medication, etc.) were excluded. Clinical, pathological, and mortality data were available for this cohort. Patients were categorized and compared according to the presence or absence of DM. RESULTS Of 132 patients with NAFLD, 44 patients (33%) had an established diagnosis of DM. Patients with DM were older and had greater serum glucose and triglyceride levels and a greater aspartate aminotransferase-alanine aminotransferase ratio. Liver biopsy specimens from patients with DM showed more vacuolated nuclei and acidophilic bodies. Cirrhosis (histological or clinical) occurred in 25% of patients with DM (11 of 44 patients) and NAFLD compared with only 10.2% (9 of 88 patients) of patients without DM with NAFLD (P = 0.04). After adjusting for potential confounders (age, body mass index, and the presence of cirrhosis), both overall mortality (risk ratio [RR], 3.30; 95% confidence interval [CI], 1.76-6.18; P = 0.002) and mortality related to liver disease (RR, 22.83; 95% CI, 2.97-175.03; P = 0.003) were greater in diabetic patients with NAFLD. Markers of hepatic dysfunction (low albumin level, high total bilirubin level, and prolonged prothrombin time) were the only independent predictors of increased mortality. CONCLUSIONS Patients with NAFLD and DM are at risk for the development of an aggressive outcome, such as cirrhosis and mortality. This study supports the potential role of insulin resistance in the development of poor clinical outcomes in patients with NAFLD.

Cytokeratin subsets can reliably distinguish Barrett's esophagus from intestinal metaplasia of the stomach

The histological distinction between intestinal metaplasia involving the distal esophagus (Barretts esophagus [BE]) and intestinal metaplasia of the stomach has important clinical implications and can be difficult even with the use of histochemical mucin stains. Cytokeratin (CK) 7 and 20 are cytoplasmic structural proteins that show restricted expression in normal and malignant epithelia of the gastrointestinal tract. The aim of this study was to determine the use of CK7 and 20 expression in the histological distinction of BE from gastric intestinal metaplasia. CK7 and 20 immunostaining was performed on randomly selected surgical resection (n = 31) and biopsy specimens (n = 34) from patients with long-segment BE and gastric resection specimens (n = 11) and gastric cardia biopsy specimens (n = 13) in patients with histological evidence of intestinal metaplasia. A unique pattern of immunoreactivity designated the Barretts CK7/20 pattern showed superficial CK20 staining and strong CK7 staining of both superficial and deep glands in 29 of 31 (94%) esophageal resection specimens and 34 of 34 (100%) esophageal biopsy specimens form patients with long-segment BE. A Barretts CK7/20 pattern was not observed in gastric cardia biopsy specimens (n = 13) or gastric resection specimens (n = 11) in patients with histological evidence of intestinal metaplasia. The sensitivity, specificity, and positive predictive value of a Barretts CK7/20 pattern for a diagnosis of long-segment BE was 97%, 100%, and 100%, respectively. CK7 and 20 reactivity patterns can reliably identify the location of intestinal metaplasia in the esophagus and stomach using histological material from both routine endoscopic biopsy and surgical resection specimens.

Dysplasia of the anal transitional zone after ileal pouch-anal anastomosis: results of prospective evaluation after a minimum of ten years.

AbstractPURPOSE: Stapling of the ileal pouch-anal anastomosis with preservation of the anal transitional zone remains controversial because of concerns about the potential risk of dysplasia and cancer. The natural history and optimal treatment of anal transitional zone dysplasia ten or more years after surgery are unknown. This study establishes the risk of dysplasia in the anal transitional zone and the outcome of a conservative management policy for anal transitional zone dysplasia, with a minimum of ten years’ follow-up after ileal pouch-anal anastomosis. METHODS: A total of 289 patients undergoing anal transitional zone–sparing stapled ileal pouch-anal anastomosis for inflammatory bowel disease between 1986 and 1990 were studied. Patients undergoing anal transitional zone–sparing ileal pouch-anal anastomosis who were studied with serial anal transitional zone biopsies for at least ten years postoperatively were included (n = 178). Median follow-up was 130 (range, 120–157) months. RESULTS: Anal transitional zone dysplasia developed in 8 patients 4 to 123 (median, 9) months after surgery. There was no association with gender, age, preoperative disease duration, or extent of colitis, but the risk of anal transitional zone dysplasia was significantly associated with cancer or dysplasia as a preoperative diagnosis or in the proctocolectomy specimen. Dysplasia was high grade in two patients and low grade in six. Two patients with low-grade dysplasia on two or more occasions after detection of low-grade dysplasia underwent completion mucosectomy and perineal pouch advancement with neo–ileal pouch-anal anastomosis. One patient with high-grade dysplasia on two occasions was to undergo completion mucosectomy, but this was not technically feasible. Partial mucosectomy with vigorous anal transitional zone biopsy was performed with close postoperative surveillance. Biopsies were negative for dysplasia. The second recently diagnosed patient with high-grade dysplasia underwent examination under anesthesia with negative anal transitional zone biopsies and will be kept under close surveillance. No cancer in the anal transitional zone was found during the study period. The 4 other patients with low-grade dysplasia on 1 or 2 occasions were treated expectantly and have been dysplasia free for a median of 119 (range, 103–133) months. CONCLUSIONS: Anal transitional zone dysplasia after stapled ileal pouch-anal anastomosis is infrequent and is usually self-limiting. Anal transitional zone preservation did not lead to the development of cancer in the anal transitional zone with a minimum of ten years of follow-up. Long-term surveillance is recommended to monitor dysplasia. If repeat biopsy confirms persistent dysplasia, mucosectomy with perineal pouch advancement and neo–ileal pouch-anal anastomosis is recommended.

The gastric cardia: fact or fiction?

Abstract OBJECTIVE: It is unclear whether the gastric cardia is present from birth or is metaplastic and develops as a result of gastroesophageal reflux disease. To this end, we evaluated the histology of the entire esophagogastric junction in consecutive pediatric autopsies to determine the presence and extent of cardiac mucosa. METHODS: The entire esophagogastric junction of 33 consecutive pediatric (≤18 yr) autopsies was examined. The precise location of the squamocolumnar junction and its relationship to the esophagogastric junction was noted in all cases. Slides were evaluated by two pathologists in a blinded fashion to look for cardiac mucosa, characterized by unequivocal periodic acid-Schiff (PAS)-positive mucous glands in a lobular configuration. Sections from the antrum and esophagogastric junction were examined for the presence of Helicobacter pylori. RESULTS: Three cases were excluded due to autolysis. The mean age of the 30 remaining patients was 6.3 yr (range: 16 days–18 yr). A regular-appearing squamocolumnar junction was identified at the esophagogastric junction in all 30 cases. Cardiac mucosa was present in all specimens (mean length: 1.8 mm; range: 1.0–4.0 mm), always on the gastric side of the esophagogastric junction. There was no significant association between patient age or gender and length of cardiac mucosa. None of the patients had a known history of gastroesophageal reflux disease or Barrett’s esophagus, and none were taking acid-suppressing medications before death. All were negative for Helicobacter pylori by Giemsa stain. CONCLUSIONS: In an unselected pediatric patient population with little or no propensity for gastroesophageal reflux disease, a short segment of cardiac mucosa was consistently present on the gastric side of the esophagogastric junction, independent of gender or age. These results support the concept that the gastric cardia is present from birth as a normal structure.

Mushroom poisoning—from diarrhea to liver transplantation

Mushroom poisoning from the genus Amanita is a medical emergency, with Amanita phalloides being the most common species. The typical symptoms of nausea, vomiting, abdominal pain, and diarrhea are nonspecific and can be mistaken for gastroenteritis. If not adequately treated, hepatic and renal failure may ensue within several days of ingestion. In this case series, patients poisoned with Amanita virosa are described with a spectrum of clinical presentations and outcomes ranging from complete recovery to fulminant hepatic failure. Although there are no controlled clinical trials, a few anecdotal studies provide the basis for regimens recommended to treat Amanita poisoning. Use of i.v. penicillin G is supported by most reports. Silibinin, although preferred over penicillin, is not easily available in the United States. In those with acute liver failure, liver transplantation can be life saving.

Can topical mitomycin prevent laryngotracheal stenosis

Objectives/Hypothesis: Early topical application of mitomycin to a laryngotracheal lesion may prevent or reduce laryngotracheal stenosis (LTS).

Equivalent function, quality of life and pouch survival rates after ileal pouch-anal anastomosis for indeterminate and ulcerative colitis.

ObjectiveTo compare the function, complications, and quality of life after ileal pouch-anal anastomosis (IPAA) for patients with indeterminate colitis (IndC) and ulcerative colitis (UC). Summary Background DataReports on the outcome of IPAA for IndC have been inconclusive because of the small numbers available for analysis. Concerns about functional outcome, infectious perineal complications, pouch loss and the development of Crohn’s disease remain, while there is no data on the quality of life after IPAA for IndC. MethodsOne thousand nine hundred and eleven patients undergoing IPAA for Ind and UC from 1983 to 1999 were evaluated. IndC was confirmed by repeat pathologic evaluation in 115 patients. Functional outcome and quality of life were assessed prospectively for all office visits (IndC = 230; UC = 5388) using previously reported systems. Complications were evaluated retrospectively. ResultsFunctional results and the incidence of anastomotic complications and major pouch fistulae were the same in UC and IndC patients. Although IndC patients were more likely to develop minor perineal fistulae, pelvic abscess, and Crohn’s disease, the rate of pouch failure was 3.4%, identical to that of UC patients. There was no clinically significant difference in quality of life, or satisfaction with IPAA surgery. Patients were equally happy to recommend surgery to IndC or UC patients, but 3% fewer IndC would undergo the same surgery again for their disease. ConclusionsWhile functional outcome, quality of life, and pouch survival rates are equivalent after IPAA for IndC and UC, there is an increase in some complications and the late diagnosis of Crohn’s disease. Over 93% of IndC patients would undergo the same procedure again, and 98% would recommend IPAA to others with IndC. Patients with IndC should not be precluded from having IPAA surgery.