Clinical Problem Solving Case: The Best is the Enemy of the Good
A 55-year-old man with controlled hypertension and hypothyroidism presents for an executive physical. Despite feeling great, his intense workouts raised concerns. Historical lab review shows a rise in hemoglobin levels prompting investigation into polycythemia, considering primary and secondary causes. Diagnostic approach includes examining EPO levels and testing for JAK2 V617F mutation to determine further management.
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MD ACP: Clinical Problem Solving Case 1 The Best is the Enemy of the Good Bimal Ashar, MD, MBA (bashar1@jhmi.edu) D. William Schlott, MD Associate Professor of Medicine Johns Hopkins School of Medicine Clinical Director, Division of General Internal Medicine Medical Director, Executive & Preventive Health Program 1
DISCLOSURES No relevant financial relationships with commercial interests 2
Case Presentation 55yo gentleman with a h/o controlled hypertension and hypothyroidism presented for an executive physical. Last seen by me 1 years prior. Noted that he felt great Had always worked out 6 days/week but now workouts more intense Plays basketball with men >30 years his junior Has been vegetarian for >20 years Asked him what he has done to feel so good?? 3
Case presentation 15 months prior to visit, he went to a health and vitality center at the suggestion of a celebrity friend Had no complaints at that time but wanted to maximize his health He had a battery of blood tests drawn and sent to a special lab 4
Historical Lab Review Outside Lab 5.0 x 103/ L 6.3 x 106/ L 18.0 g/dL 194 x 103/ L 18 months prior 3.4 x 103/ L 5.73 x 106/ L 15.7 g/dL 169 x 103/ L WBC RBC Hgb Platelet Why the rise in hemoglobin? 5
Polycythemia WHO definition--Hgb>16.5 g/dL in men and >16.0 g/dL in women Primary--caused by a mutation (either acquired or inherited) in RBC progenitor cells Polycythemia vera, myeloproliferative neoplasms Secondary--caused by elevated serum erythropoietin (EPO) Hypoxia COPD, shunts, sleep apnea, CO poisoning Renal post transplantation, renal cysts, renal artery stenosis Tumors hepatocellular CA, Renal cell CA, pheo, fibroids Athletic performance enhancers ESAs, blood doping, androgens 6
Diagnostic Approach to Polycythemia EPO level elevated No Yes Search for secondary cause Test for JAK2 V617F mutation pos neg PV likely Refer 7
Vitality Center 1st visit (drawn at 1:30 pm) Glucose Vitamin B12 TSH Free T4 Free T3 Reverse T3 Anti-TPO Ab Creatinine NT-proBNP 25 (OH) Vit D 74 >2000 1.93 1.21 3.1 9 92 1.0 10 27 DHEA-S FSH LH Testosterone Free T SHBG Prolactin 65 6.5 6.4 286 5.84 31 6.01 Does he have hypogonadism? 8
Intervention? He was diagnosed with hypogonadism and testosterone pellets were implanted around his left hip He was also started on monthly IV vitamin infusions and sold 8 supplements to take daily 9
Diagnosis of Hypogonadism Signs/symptoms necessary to make diagnosis (e.g., erectile dysfunction, decreased libido, fatigue, decreased muscle mass, gynecomastia, osteoporosis) An abnormal total testosterone should be repeated at least once Fasting testosterone level from 8-10 am should be drawn to account for diurnal fluctuation No true cutoff for low T (<300 ng/dl generally accepted) 10
Diurnal Variation Bremner WJ, Vitiello MV, Prinz PN. J Clin Endocrinol Metab 1983; 56:1278 11
Postprandial Variation Clinical Endocrinology, Volume: 78, Issue: 2, Pages: 291-296, First published: 17 July 2012, DOI: (10.1111/j.1365-2265.2012.04486.x) 12
Our Patient Signs/symptoms necessary to make diagnosis (e.g., erectile dysfunction, decreased libido, fatigue, decreased muscle mass, gynecomastia, osteoporosis) X An abnormal total testosterone should be repeated at least once X Fasting testosterone level from 8-10 am should be drawn to account for diurnal and postprandial fluctuations X 13
Causes of Hypogonadism Type Lab Values Causes Primary Low Testosterone Increased LH and FSH Congenital (Klinefelter) or acquired (orchitis, torsion, chemo) Secondary Low Testosterone Low or normal LH and FSH Congenital (Prader-Willi) or acquired (opioids, pituitary tumors, trauma) Mixed Low Testosterone Typically normal LH and FSH Aging, HIV, DM, COPD, obesity 14
Forms of Testosterone (none approved for age-related low T) Formulation Comments Intramuscular Variety of preparations given every 2-14 weeks Transdermal patches 2-6 mg/d. Can cause rash. Transdermal gels/solutions Potential for skin transfer with direct contact Buccal testosterone Can cause gum irritation Subcutaneous implants (pellets) 75 mg/pellet (2-6 pellets initially but optimal dosing unclear). Can cause infection and fibrosis. Dosing every 3-4 months. Approved 3/2019 Oral testosterone (Jatenzo) 15
Testosterone Prescriptions Estimated 400% increase in T prescriptions between 2001 and 2011 Most prescriptions appear to be for age- related low T even though off label One claims study done by the FDA suggested that 28% of men with newly prescribed T had no prior evidence of testosterone level measurement 16
ACP Guideline for Treatment of Age-Related Low T Can discuss risks/harms of T replacement for age-related low T w/sexual dysfunction (low certainty evidence) Discontinue if no benefit in 12 months Consider IM rather than transdermal given cost ($156 vs. $2135 annually) Do not initiate T replacement to improve energy, vitality, physical function, or cognition Ann Intern Med 2020;172:126-133 17
Back to Our Patient Felt great after infection cleared up Blood work: 1 month post implant 3 months post implant Total T 960 ng/dl 683 ng/dl Free T 26 H 18 ng/dl LH Undetectable L FSH Undetectable L Undetectable L Hemoglobin 15.8 g/dL 18
Back to Our Patient He had more pellets inserted (unclear how many) after 3 month visit He went back to the clinic complaining that my balls are shrinking What is going on? 19
Back to the Clinic Started on self-administered human chorionic gonadotropin (HCG) injections twice per week 20
HCG Actions virtually identical to pituitary LH Stimulates LH receptors on Leydig cells to increase testosterone production May stimulate spermatogenesis FDA approved for Treatment of prepubertal cryptorchidism Select cases of secondary hypogonadism (especially if fertility is desired) 21
Our Patient Kept returning for pellet implantation about every 3 months since he was feeling great Testicular size began to increase but not to their prior level Total testosterone up to 1030 ng/dl Hemoglobin raised to 18 g/dl What do we do now? 22
Testosterone Adverse Effects Erythrocytosis Endocrine Society guidelines suggest stopping in patients with HCT > 54% Prostate cancer Probably does not cause but avoid in patients with prostate cancer Venous thromboembolism Cardiovascular studies inconclusive yet FDA has mandated labeling of all T products reflect possible increase risk of stroke and heart attack 23
Back to the Clinic Regular phlebotomy started Pellets continued HCG continued How would you advise the patient? 24
Back to My Visit BP 153/83 (previously 128/80 18 months prior) Body fat% ~22 Hgb 16.6 with iron deficiency from phlebotomy My recommendations: Stop further testosterone pellet therapy and HCG injections Establish with an endocrinologist to titrate levels Continue with phlebotomy to get hemoglobin under 16 (about his baseline) Stop vitamin infusions and supplements Follow blood pressures very closely. May need to increase medications 25
10 Days Later Presented to an ER with right sided numbness and weakness MRI showed left thalamocapsular stroke Recovered over a few weeks 26
6 Months Later His lawyer called wanted to discuss lawsuit against the wellness center 27
Learning points The diagnosis of hypogonadism should include signs/symptoms and repeat low fasting levels of testosterone Testosterone treatment for age-related hypogonadism is off-label but may be reasonable for patients with sexual dysfunction Testosterone is often inappropriately prescribed HCG is sometimes given to counteract testosterone- induced testicular hypofunction (also off-label) Erythrocytosis is probably the most common side effect so hemoglobin/hematocrit should be monitored closely 28
Clinical Problem Solving Case 2: Blood and Spice 29
Case Presentation 48yo man presented to establish care. Complaints included: Bilateral hand pain for years. Thinks it is worsening. No redness. Denies swelling. Some early morning stiffness resolves within 15 Snoring. Wife wanted him to mention that he stops breathing at times. Erectile dysfunction and decreased libido. Has been going on for 1-2 years. SH: 14 pack-year smoking (quit recently). 10 drinks/week. No drug use. Works as an electrician. 30
Physical exam VS: Pulse 70, BP-168/90, BMI-31 GU: Normal testicular size and firmness. No nodules. Prostate normal size w/o nodules Extremities: Bilateral diffuse prominence of MCPs, PIPs, and to a lesser extent DIPs. No warmth or erythema. Decreased ability to make a fist Skin and nails: No abnormalities noted DDx? 31
Hand Arthropathy Psoriatic arthritis DIPs Gout/pseudogout 32
X-ray Report Bilateral, prominent proliferative changes involving the metacarpal heads, 1st IP joints, PIP greater than DIP joints, accompanied by erosive changes involving the proximal phalanges but relative sparing of the joint spaces at this time. Although the proliferative changes are consistent with osteoarthritis, the erosive pattern is suggestive of crystalline (such as gout) or inflammatory arthritis (such as psoriatic or Reiter's syndrome). 33
LABS CBC-normal Creatinine-0.7 AST- 39 ALT- 86 Alk phos- 96 Testosterone-396 Iron 268 (65-170) TIBC 276 (250-450) Transferrin saturation 97% Ferritin 1450 (10-300) RF-normal 34
Liver Bx and Genetic Test MARKED HEPATOCELLULAR AND BILIARY EPITHELIAL HEMOSIDERIN ACCUMULATION. MILD PORTAL FIBROSIS, BUT NO EVIDENCE OF ESTABLISHED CIRRHOSIS. MODERAT E FAT ACCUMULATION AND NUMEROUS GLYCOGEN NUCLEI. Tissue iron 18796 mcg/g (400-2200) HFE-C282Y homozygote 35
Clinical Manifestations of HH Liver Elevated LFTs, hepatic fibrosis that can go on to cirrhosis, hepatocellular CA Heart Dilated cardiomyopathy, diastolic dysfunction, conduction disturbances Endocrine Type II DM, secondary hypogonadism, secondary hypothyroidism Arthropathy Hands or other joints Bronze skin-iron deposition + melanin Susceptibility to infection Yersinia enterocolitica, Vibrio vulnificus Cancer risk--?increased risk colon and breast CA 36
Treatment Course Underwent about 42 phlebotomies in a year to get his ferritin under 50. Would get phlebotomy every 2 months with fairly stable ferritin levels 37
Something happened 30 15 14.5 25 14 20 13.5 15 13 10 12.5 5 12 Phlebotomy 0 11.5 Jun-17 Jul-17 Aug-17 Sep-17 Oct-17 Nov-17 Dec-17 Ferritin Hgb 40
Work-up Colonoscopy and EGD negative for bleeding source Small bowel video capsule endoscopy no bleeding source No other bleeding source found Ferritin remained in high 20s/low 30s without any further phlebotomy ??? 41
Took more history Asked about any OTC meds/supplements High-dose turmeric started shortly after his last phlebotomy (7/17) He thought it was helping his arthritic pain 42
Turmeric Challenge 80 70 60 50 Turmeric 40 30 20 Turmeric stopped 10 0 Dec-18 Jan-19 Feb-19 Mar-19 Apr-19 May-19 Jun-19 Ferritin 43
Turmeric and Iron Curcumin binds ferric iron (Fe3+) to form a ferric-curcumin complex Can act as an iron chelator Has been shown to induce iron deficiency in mice One case report of iron deficiency anemia developing with use of high-dose turmeric (Cureus. 2019 Jan; 11: e3858) 44
Learning Points Fairly limited differential diagnosis for hand arthropathy Think about hemochromatosis (HC) in patients with prominent involvement of MCPs Phlebotomy is a safe and effective treatment for HC but does not typically effect the progression of arthritis Turmeric may cause iron deficiency and may have a role in maintaining iron levels in patients with HC? 45
