THE LINCOLN HOSPITAL MEDICINE BLOG

46 Year Old Patient Diagnosed with Latent Autoimmune Diabetes in the Adult (LADA). 

Cesar A López, MD; Mohan Vinuta M.D. 

Introduction:

Latent Autoimmune Diabetes in Adults (LADA) also named slowly progressing insulin dependent diabetes or type 1.5 diabetes, is a type of diabetes with a prevalence approximately of 10% non-insulin-requiring diabetics, and is characterized by the presence of a type 2 diabetic phenotype combined with islet antibodies. Diagnosis is made by 3 features: Diagnosis of diabetes in a patient who is more than 30 years old, the presence of diabetes-associated autoantibodies and not treated with insulin during the first 6 months of diagnosis of hyperglycemia. ß-cell dysfunction is rapidly progressing depending on concentration and number of diabetes-associated autoantibodies, characterized by immeasurable fasting C-peptide and the requirement of insulin with in 3-6 years. The following case report shows a typical case of a 46 year old patient diagnosed 2 years earlier with diabetes type 1 after he had multiple admissions due to hyperglycemia. Phenotype was of a type 1 diabetes, but age of diagnosis and the presence of hyperglycemia with out DKA or HHS prior to diagnosis was consistent more with a type 2 diagnosis. 

Case Report:

Discussion:

In 1986, was reported a subgroup of type 2 diabetic patients who, despite having islet autoantibodies, showed preserved ß-cell function. The type of diabetes in these patients was referred to as latent type 1 diabetes, showing clearly different features from classic type 1 and classic type 2 diabetes. Later was launched the term latent autoimmune diabetes in adults (LADA) for this slowly progressive form of autoimmune diabetes initially managed with diet and oral hypoglycemic agents before becoming insulin requiring. This form of diabetes has also been called slowly progressing insulin dependent diabetes or type 1.5 diabetes.

LADA is the defined as a type 2 diabetic phenotype combined with islet antibodies diagnosed by three features including: adult age at diagnosis (>30 years of age), the presence of diabetes-associated autoantibodies (at least one of the four antibodies commonly found in type 1 diabetic patients: ICAs, autoantibodies to GAD65, IA-2, and insulin), and not treated with insulin within the first 6 months after diagnosis to manage hyperglycemia.

Although LADA patients by definition are not insulin requiring at and during the first time after diagnosis of diabetes, within 6 years, ß-cell function is severely impaired, leading to insulin dependency. Nevertheless, ß-cell failure, defined as immeasurable fasting C-peptide, may take up to 12 years until it occurs in patients with islet antibodies.

High concentrations of islet antibodies predict future ß-cell failure or destructive process, whereas a low number of islet antibodies, particularly lack of ICAs, is associated with lack of progression to ß-cell failure, hence it shows that the presence of two or three islet antibodies at diagnosis predicts severe deterioration in ß-cell function within 5 years and the presence of only ICAs or only GADAs is associated with severe deterioration within 12 years. Progression to insulin dependence in LADA patients is more rapid in those aged younger than 45 yr than in older cases.

The natural course of these patients shows that C peptide will decrease with time in parallel with the curve for C peptide as in classical type 1 diabetic patients, and most of the LADA patients will require insulin within three years.

It is suggested that insulin deficiency as well as insulin resistance both participate in the course of LADA, because the frequency of metabolic syndrome is higher that in the general population but less prevalent than in type 2 diabetic patients.

Conclusions:

Although the presence of LADA in the diabetic populations is high (at least 10%), the diagnosis of this affection is not normally done, despite having only 3 requirements to be made to achieve this goal: Adult onset diagnosis of diabetes, the presence of diabetes-associated autoantibodies and not treated with insulin within the first 6 months after diagnosis to manage hyperglycemia.

Prospective follow-up of these patients shows that complete ß-cell failure occurs in almost all of these patients, but it may take up to 12 years until it develops depending on concentration and quantity of this antibodies.  Although not insulin requiring at diagnosis, patients who are positive with islet cell antibodies have impaired ß-cell function. Hence, insulin is the treatment of choice and indicated since the time of diagnosis.

As seen in our example, not all patient with diabetes can be made to fit only the typical diagnosis of type 1 insulin requiring and type 2 not insulin requiring diabetes, with the increase in incidence of diabetes in our population due to the obesity epidemic, probably the greatest area of confusion will involve the distinction of LADA from other types of diabetes occurring in individuals over the age of 30–35 years.

ISOPROPYL ALCOHOL INTOXICATION – A RARE PRESENTATION

Seema Karanjgaokar MD, Benjamin Francisco MD

 Isopropyl alcohol is a widely used solvent in industry and is also commonly used as a disinfectant. It can be found in many mouthwashes, skin lotions, and rubbing alcohol. Intoxication is known in adults through ingestion and inhalation and is more common in children by absorption via the skin. We present a case of an adult male who had isopropyl alcohol intoxication due to absorption via the skin.

Case Report

The patient is a 53 year old male with history of psoriasis who was found unresponsive by his mother on the morning of admission. He was very drowsy and lethargic, responsive only to deep noxious stimuli. He did not respond to narcan, thiamine, or dextrose but was able to maintain his airway. He had active denuded lesions of psoriasis throughout his body including his arms, legs, back, and chest. Two bottles of 70% isopropyl alcohol were found next to him that morning and the patient was found wearing an alcohol soaked sweater and pants. He was covered in a transparent plastic wrap all over the body including the scalp, with only the face being exposed. Labs showed a normal anion gap acidosis, elevated creatinine, an elevated serum osmolar gap, and negative ethyl alcohol levels. The patient was admitted to ICU for close observation. He subsequently developed rhabdomyolysis and related electrolyte abnormalities, which improved on fluid administration. He did not have any need for dialysis and the osmolar gap in the serum improved along with the acidosis and renal function.

DISCUSSION

Isopropyl alcohol is a common agent used in disinfectants and rubbing alcohol. Isopropyl alcohol causes cardiovascular and CNS depression, mild acidosis, and hypoglycemia. Other symptoms include dizziness, poor coordination, headache, confusion, gastric irritation, abdominal pain, vomiting, haematemesis, hypotension, tachycardia, and loss of deep tendon reflexes. Isopropyl alcohol toxicity through skin absorption has been documented in infants and small children. However, toxicity in adults is generally from ingestion of isopropyl alcohol, specifically as a substitute for ethanol. The case we describe is unique in its presentation since isopropyl alcohol intoxication is rarely found in adults due to skin absorption. Our patient had intoxication due to the concomitant presence of psoriasis, which resulted in rapid absorption through denuded skin.

Distal Ileitis: A rare complication of 5-FU based chemotherapy 

Haimesh Shah, MD; Jay Nayak, MD; Beena Sattar, MD; Niyati Bhagwati, MD 

Introduction:

5-Fluorouracil (5-FU) is the most widely used agent for the treatment of colon, breast, stomach and pancreatic cancer. Diarrhea is reported in 15-20% of patients being treated with 5-FU, affecting quality of life. We describe a rare case of distal ileitis in a patient receiving 5-FU based chemotherapy.

Case Report:

A 74 year old Hispanic male with a history of sigmoid cancer treated surgically and newly diagnosed invasive rectal adenocarcinoma (six weeks prior to this admission), managed with 5-FU based chemotherapy and external beam radiotherapy to the pelvis, presented on the third day of his second cycle with complaints of diffuse lower abdominal pain and diarrhea. Physical exam was significant for tenderness to palpation in the lower abdominal area and all the laboratory work-up were within normal limits. Computerized tomography revealed thickened distal ileum consistent with enteritis. Subsequent colonoscopy showed normal colonic mucosa with no skip lesions, peyer’s patches and normal terminal ileum with no ulceration. Biopsy of the terminal ileum revealed atypical mucosal changes, which were consistent with chemotherapy induced ileitis. His 5-FU pump was removed and he was managed conservatively with bowel rest and intravenous hydration. His symptoms gradually resolved and was discharged home. He was stable on subsequent follow-ups.

Conclusion:

Distal ileitis is a very rare complication of 5-FU, which should be considered early in the differential in patients presenting with diarrhea or signs and symptoms of small bowel obstruction. Withholding the treatment temporarily, followed by subsequent re-challenge after clinical stabilization is the preferred approach in this selected group of patients.

Harbingers of Doom in Colon Cancer: Young Age, Beta hCG Production and “Signet Ring” Histology 

Beena Sattar, MD;  Tarun K. Narang, MD; Doru Paul, MD

Introduction:

Young age, b-hCG secretion and ‘signet-ring’ histology in patients with colorectal cancer (CRC) are independently associated with advanced disease and poor prognosis. We present a young patient with ‘signet-ring’ cell metastatic colon cancer associated with persistent elevation of serum b-hCG and positive tumor immuno-histochemistry.

Case:

A 23 year old woman with a 9 month history of abdominal distension presented with acute worsening and pain. Significant ascitis was present and urine b-hCG was positive. Ultrasound revealed no evidence of gestation. Serum b-hCG was 4693 mIU/ml. There was no family history of malignancy.  On laparotomy, 1.4L of fluid was removed.  Fluid cytology revealed an adeno-carcinoma that stained positive for b-hCG. A 5 cm mass was seen in the transverse colon. The mesentery, stomach, diaphragm and ovaries were studded with tumor implants. Extensive surgery including transverse colon resection was performed. Histology revealed ‘poorly differentiated adeno-carcinoma’ arising in colonic glandular epithelium, with ‘signet- ring’ and mucinous features. Tumor immuno-histochemistry was positive for B-hCG. Post surgery, b-hCG dropped to 470. AFP and CEA levels remained normal.  Follow-up PET scan after 6 cycles of chemotherapy showed clearing peritoneal deposits with persistent ascitis. B-hCG then declined to 58. The patient missed chemotherapy for a month and was re-admitted with intra-hepatic biliary obstruction. Vaginal bleeding prompted an endometrial biopsy, which revealed metastasis with ‘signet-ring’ features. B-hCG elevation was seen again with levels up to 268. Subsequently, she was readmitted with intractable vomiting and developed multiple infections. Despite aggressive chemotherapy, her disease progressed, and thereafter, palliative care was initiated.

Discussion:

Poor outcomes in young adults with CRC are associated with striking biological and histological differences. ‘Signet-ring’ cell cancer, a variant of mucinous adeno-carcinoma, is common in this population. It is associated with advanced stage of disease at diagnosis and has a worse prognosis. Tumor markers predict tumor behavior and possibly etiology. B-hCG in CRC indicates poor differentiation, local invasion, metastasis and decreased survival. T cell suppression and b-hCG mediated humoral immune response modulation are postulated mechanisms.

Conclusion:

Our case demonstrates that young age, b-hCG production and ‘signet-ring’ histology are associated with worse outcomes due to aggressive tumor behavior, even in the absence of family history.  Persistence of b-hCG after treatment, may indicate residual tumor mass. In order to optimize care, further research is needed to unravel the pathogenic pathways involved in this rare form of cancer.

Imatinib Response in C-Kit Negative Gastrointestinal Stromal Tumor

Haimesh Shah, MD; Caroline Hwang, MD; Doru Paul, MD

Introduction:

Gastrointestinal stromal tumors (GIST), a form of mesenchymal tumors, are characterized by oncogenic KIT mutation. Up to 10% of C-Kit negative GISTs are reported, which may have activating platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib has been approved for the treatment of C-Kit positive GIST, with limited data in C-Kit negative tumors. We report a case of C-kit negative GIST responding to imatinib at 3-months follow-up.

Case Report:

A 70 year old male, with no significant medical history, presented with complains of upper abdominal pain radiating to the back, early satiety and weight loss over few months. Physical examination was significant for pale conjunctiva, distended abdomen with positive flank dullness, and a poorly defined palpable non-tender epigastric mass with absent lymphadenopathy. The laboratory tests were only significant for anemia of chronic disease and normal CEA, and CA 19-9 levels. CT scan of the abdomen and pelvis showed a large mass related to the head and body of the pancreas, and compressing the stomach. A CT-guided biopsy was consistent with GIST, and immunohistochemistry was negative for C-kit. He underwent a PET scan, which revealed two large partially necrotic masses, one emanating from the greater curvature of the stomach (18cm x 11cm x 15cm), and the other adjacent to the stomach (9.8cm x 8.3cm). His tumor was unresectable and was started on imatinib (400mg/day orally). After receiving 6 weeks of imatinib, a follow-up CT scan showed a decrease in the tumor bulk. He was continued on imatinib and at 3 months, PET scan showed a marked decrease in size of both the masses (12cm x 10cm x 9cm, and 3.7cm x 4.4 cm, respectively). Based on his clinical response, we decided to continue imatinib and monitor response to therapy.

Conclusion:

The use of imatinib in C-kit negative, imatinib-sensitive PDGFRA oncoproteins have been reported in 3 patients with a partial response rate of 66.7%, though limited data exists. Our case demonstrates that imatinib can be a viable option for patients with unresectable C-kit negative GIST and may be considered in the treatment option. Another approach could be to check in-vitro analysis for PDGFR status and imatinib sensitivity. In situations where such tests are not available, the use of imatinib may not be withheld in this subset of patients.’